WO2020088194A1 - 抑制rip1激酶的杂环酰胺及其用途 - Google Patents

抑制rip1激酶的杂环酰胺及其用途 Download PDF

Info

Publication number
WO2020088194A1
WO2020088194A1 PCT/CN2019/109899 CN2019109899W WO2020088194A1 WO 2020088194 A1 WO2020088194 A1 WO 2020088194A1 CN 2019109899 W CN2019109899 W CN 2019109899W WO 2020088194 A1 WO2020088194 A1 WO 2020088194A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkylene
compound
alkyl
nhc
formula
Prior art date
Application number
PCT/CN2019/109899
Other languages
English (en)
French (fr)
Inventor
周兵
唐炜
杨向波
路慧敏
高梦颖
杨亚玺
冯慧瑾
Original Assignee
中国科学院上海药物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201910712428.1A external-priority patent/CN111138448B/zh
Application filed by 中国科学院上海药物研究所 filed Critical 中国科学院上海药物研究所
Priority to US17/289,642 priority Critical patent/US11498927B2/en
Priority to JP2021524263A priority patent/JP7045526B2/ja
Priority to EP19879421.6A priority patent/EP3872077B1/en
Publication of WO2020088194A1 publication Critical patent/WO2020088194A1/zh
Priority to US18/045,149 priority patent/US20230167129A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a heterocyclic amide compound and uses thereof. Specifically, the present invention relates to a heterocyclic amide which inhibits RIP1 kinase and uses thereof.
  • Receptor interacting protein 1 (RIP1) kinase is a TKL family serine / threonine protein kinase involved in innate immune signaling.
  • RIP1 kinase is a protein-containing RHIM domain that has an N-terminal kinase domain and a C-terminal death domain.
  • the RIP1 death domain mediates interaction with other death domain-containing proteins, including Fas and TNFR-1, TRAIL-R1 and TRAIL-R2 and TRADD, while the RHIM domain pair binds to other RHIM domain-containing Proteins are critical, such proteins as TRIF, DAI and RIP3, and achieve many of their functions through these interactions.
  • RIP1 is a central regulator of cell signaling, which is involved in mediating both pro-survival and programmed cell death pathways, discussed in detail below.
  • RIP1 in cell signaling has been evaluated under different conditions, but the best understanding can be obtained in the mediated signaling downstream of the death receptor TNFR1.
  • TNFS cohesion is achieved through TNF, leading to oligomerization, and multiple proteins, including linear K63-linked polyubiquitinated RIP1, TRAF2 / 5, TRADD and cIPAs, are recruited to the cytoplasmic tail of the receptor.
  • This complex which is dependent on RIP1, serves as a scaffold protein (ie, kinase-independent), called complex 1, which provides a platform for pro-survival signaling by activating the NF- ⁇ B and MAP kinase pathways.
  • DISC death-inducing signaling complex
  • DAMP Danger-Related Molecular Patterns
  • RIP3 knockout mice where RIP1-mediated programmed necrosis is completely blocked
  • Necrotatin-1 a tool inhibitor of RIP1 kinase activity with poor oral bioavailability
  • the abnormal regulation of kinase-mediated programmed cell death is related to various inflammations.
  • RIP3 knock-out mice have been shown to have an effect on inflammatory bowel disease (including ulcerative colitis and Crohn's disease), photoreceptor cell necrosis induced by retinal detachment, retinitis pigmentosa, acute pancreatitis and sepsis induced by bursin Systemic inflammatory response syndrome (SIRS) has a protective effect.
  • SIRS bursin Systemic inflammatory response syndrome
  • Necrotatin-1 has been shown to effectively relieve ischemic brain injury, retinal ischemia / reperfusion injury, Huntington's disease, renal ischemia-reperfusion injury, cisplatin-induced kidney injury and traumatic brain injury.
  • Other diseases or conditions that are at least partially regulated by RIP1-dependent apoptosis, necrosis, or cytokine production include malignant tumors of blood and solid organs, bacterial and viral infections, and Gaucher disease, etc.
  • the present invention provides compounds of general formula (I), pharmaceutically acceptable salts, stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, Racemate, polymorph, solvate or isotopically labeled compound:
  • X is O, S, SO, NH, CO, CH 2 , CF 2 , CH (CH 3 ), CH (OH) or N (CH 3 );
  • Y is C 1 -C 2 alkylene (ie CH 2 or CH 2 CH 2 );
  • Ring A is a benzene ring, 5-6 membered heteroaromatic ring, 5-6 membered non-aromatic heterocyclic ring or
  • the connected carbonyl moiety and L 1 are respectively connected to the interphase position of ring A;
  • R A is H or C 1 -C 4 alkyl
  • L 1 is C 3 -C 6 alkyl, C 3 -C 6 alkoxy, halogenated C 3 -C 6 alkoxy, C 3 -C 6 alkenyl, C 3 -C 6 alkenyloxy, or among them
  • L is O, S, NH, N (CH 3 ), CH 2 , CH 2 CH 2 , CH (CH 3 ), CHF, CF 2 , CH 2 O, CH 2 N (CH 3 ), CH 2 NH or CH (OH);
  • Ring B is C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heteroaryl or 5-6 membered non-aromatic heterocyclic group; the C 3 -C 6 cycloalkyl, phenyl, 5- 6-membered heteroaryl or 5-6 membered non-aromatic heterocyclic groups are each independently unsubstituted or substituted with one or two substituents each independently selected from halogen, C 1 -C 4 alkyl, Halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, nitro and C 1 -C 4 alkyl C (O)-;
  • R 2 is H or CH 3 ;
  • Ring M is independently a C 6 -C 10 aromatic ring or a 5-10 membered heteroaromatic ring
  • Each occurrence of R a is independently hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group, C 3 -C 10 cycloalkyl, or C 5 -C 10 cycloalkenyl; the C 1 -C 6 alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic Heterocyclyl, C 3 -C 10 cycloalkyl, or C 5 -C 10 cycloalkenyl are each independently unsubstituted or substituted by 1 or 2 amino, hydroxyl, C 1 -C 4 alkoxy, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or CN substitution;
  • M a is independently C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group, C 3 -C 10 cycloalkyl, or C 3 -C 10 cycloalkenyl; said C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group, C 3 -C 10 cycloalkyl, or C 3 -C 10 cycloalkenyl groups are each independently unsubstituted or substituted with one or two substituents each independently selected from the following: halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, -CN;
  • n1 is 0, 1 or 2 independently for each occurrence
  • R is independently hydrogen, C 1 -C 10 alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group, C 3 -C 10 cycloalkyl , Or C 3 -C 10 cycloalkenyl; the C 1 -C 10 alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group, C 3 -C 10 cycloalkyl, or C 3 -C 10 cycloalkenyl is each independently unsubstituted or substituted with 1-4 M d ;
  • Each occurrence of M d is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -CN, NO 2 , SCF 3 , oxo, -OM e , -OC (O) M h , -OC (O) NM f M g , -SM e , -S (O) 2 M e , -S (O) 2 NM f M g , -C (O) M e , -C (O) -5-10 membered monocyclic heterocyclic ring, -C (O) -5-10 membered monocyclic heteroaryl group, -C (O) OM e , -C (O) NM f M g , -NM f M g , -N (M e ) C (O) M h , -
  • two M d on the same carbon can form a 3-8 membered saturated or unsaturated ring together with the ring atoms connected to it, thereby forming a spiro ring structure;
  • the two M d on the adjacent carbon can form a 3-8 membered saturated or unsaturated ring together with the ring atoms connected to it, thereby forming a parallel ring structure;
  • the two M d on the interphase carbon can form a 3-8 membered saturated or unsaturated ring together with the ring atoms connected to them, thereby forming a bridge ring structure.
  • the compound of formula I is a compound represented by formula Ia or Ib:
  • Z 1 is N, CH, C (CH 3 ), or C (halogen);
  • Z 2 is N, or CR 1 ;
  • Z 3 is N, CH, C (CH 3 ), or C (halogen); and Z 1 , Z 2 , and Z 3 cannot be N at the same time;
  • Z 4 is O, CR 1 , S, N, or NR 1 ;
  • Z 5 is O, CR 1 , S, N, or NR 1 ;
  • A, L 1 , X, Y, R, R A , R 1 , R 2 are as defined in the general formula I described above when they occur;
  • the compound of formula I is a compound represented by formula Ic, Id, Ie, or If:
  • Z 1 is N, CH, C (CH 3 ), or C (halogen);
  • Z 2 is N, or CR 1 ;
  • Z 3 is N, CH, C (CH 3 ), or C (halogen); and Z 1 , Z 2 , and Z 3 cannot be N at the same time;
  • Z 4 is O, CR 1 , S, N, or NR 1 ;
  • Z 5 is O, CR 1 , S, N, or NR 1 ;
  • a 2, A 3, and A 5 are each independently selected from: CR A, O, S, N , and NR A to form a furyl, thienyl, isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl Radical, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, or tetrazolyl ring moiety, where at most one R A is not hydrogen;
  • a 6 , A 7 , A 8 , and A 9 are each independently CR A , where at most one R A is not hydrogen;
  • a 6 , A 7 , A 8 , and A 9 is N, and the other A 6 , A 7 , A 8 , and A 9 are CH;
  • a 6, A 7, A 8 , A 9, and one is N + -O -, and the other A 6, A 7, A 8 , and A 9 are CH;
  • L 1 , X, Y, R, R A , R 1 , R 2 when present are the same as defined in the general formula I described above.
  • the N + -O - in A 6 to A 9 means that N and a ring atom form a bond between a normal onium ion and an O - ion.
  • the compound of formula I is a compound of formula Ig or Ih:
  • R 1 is H, halogen, -OH, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy;
  • X is O, S, CH 2 , NH or N (CH 3 );
  • a 2, A 3, and A 5 are each independently selected from: CR A, O, S, N , and NR A to form a furyl, thienyl, isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl Radical, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, or tetrazolyl ring moiety, where at most one R A is not hydrogen;
  • L 1 , R, R A appear as defined in the general formula I described above;
  • the compound of formula I is a compound of formula Ii or Ij:
  • R 1 is H, halogen, -OH, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy;
  • X is O, S, CH 2 , NH or N (CH 3 );
  • a 6 , A 7 , A 8 , and A 9 are each independently CR A , where at most one R A is not hydrogen;
  • a 6 , A 7 , A 8 , and A 9 is N, and the other A 6 , A 7 , A 8 , and A 9 are CH;
  • a 6, A 7, A 8 , A 9, and one is N + -O -, and the other A 6, A 7, A 8 , and A 9 are CH;
  • L 1 , R, and R A are as defined above in Formula I as described above.
  • the N + -O - in A 6 to A 9 means that N and a ring atom form a bond between a normal onium ion and an O - ion.
  • the compound of formula I is a compound of formula Ik or Il:
  • R 1 is H, F, Cl, CH 3 , CH 2 CH 3 ;
  • R is isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, C 3 -C 6 cycloalkyl, They are each independently unsubstituted or substituted with 1 F, Cl, methyl, ethyl, isopropyl or cyclopropyl.
  • the compound of the general formula I is a compound represented by the formula Im or In:
  • R 1 is H, F, Cl, CH 3 , CH 2 CH 3 ;
  • X is O, S, or CH 2 ;
  • R is C 1 -C 6 alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-7 membered non-aromatic heterocyclic group, C 3 -C 8 cycloalkyl, or C 5- C 8 cycloalkenyl; the C 1 -C 6 alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-7 membered non-aromatic heterocyclic group, C 3 -C 8 cycloalkane Radicals, or C 5 -C 8 cycloalkenyl groups are each independently unsubstituted or substituted with 1-4 M d ;
  • M d is selected from F, Cl, methyl, ethyl, propyl, butyl, trifluoromethyl,-(C 1 -C 6 alkylene) -OH, isopropyl, cyclopropyl, hydroxy, methyl Oxygen, amino, methylamino, dimethylamino, diethylamino, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-6 membered non-aromatic heterocyclic group; wherein C 6- C 10 aryl, 5-10 membered heteroaryl, 3-6 membered non-aromatic heterocyclic group, each independently unsubstituted or substituted by one or two substituents each independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, -CN.
  • the compound of formula I is selected from the following compounds:
  • the isotopically labeled compound is, for example, a deuterium substituted compound.
  • Isotope-labeled compounds can be used in applications such as metabolic detection.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) selected from the present invention, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer
  • a pharmaceutically acceptable salt thereof an enantiomer, a diastereomer
  • isomers, atropisomers, optical isomers, racemates, polymorphs, solvates, or isotope-labeled compounds and optionally, pharmaceutically acceptable Carrier.
  • the compounds of the present invention are particularly effective for the treatment of RIP1 kinase-mediated diseases or disorders.
  • RIP1 mediated diseases or disorders are those mediated by the activation of RIP1 kinase; therefore, the inhibition of RIP1 kinase is beneficial for the treatment of these diseases or disorders.
  • the compounds of the invention can be used to treat diseases / conditions that may be at least partially regulated by programmed necrosis, especially inflammatory bowel disease (including Crohn's disease, ulcerative colitis), psoriasis, retinal detachment, pigment Retinitis, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spinal arthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren's syndrome, provincial scleroderma, antiphospholipid syndrome, Vasculitis, osteoarthritis, non-alcoholic fatty liver hepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary hard cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, solid organ Ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Hunt
  • the compound of formula (I) is prepared by treating the aryl halide (formula Ia-1, wherein the halogen is Cl, Br, or I) with an alkynyl compound containing the R group (formula II) under Sonogashira coupling conditions.
  • the coupling reaction is achieved in the presence of a metal catalyst (including but not limited to a combination of a metal palladium catalyst and a metal copper catalyst) and a base, and in an appropriate solvent at an elevated temperature (eg, about 80 ° C to 150 ° C) .
  • the reaction can be promoted by microwave radiation.
  • the metal palladium catalyst includes but is not limited to bis (triphenylphosphine) palladium (II) dichloride, allylic palladium (II) chloride dimer, [1,1'-bis (diphenylphosphino ) Ferrocene] palladium dichloride ((dppf) PdCl 2 ), palladium (II) acetate.
  • the metal copper catalyst includes but is not limited to cuprous iodide. Examples of suitable bases that can be used include, but are not limited to, triethylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).
  • Non-limiting examples of suitable solvents include N, N-dimethylformamide, dimethylacetamide, methanol, ethanol, acetonitrile, dimethoxyethane, dimethyl sulfoxide, dioxane, tetrahydrofuran, Ethylene glycol dimethyl ether, toluene.
  • the Boc-L-serine is reacted with a suitably substituted 1-fluoro-2-nitrobenzene with a base to obtain I-1, and then the nitro group is reduced to the amine I-2 (reduction conditions such as but not limited to Zn / AcOH, Fe / NH 4 Cl / EtOH, Zn / NH 4 Cl / EtOH,), and use condensation reagents to perform intramolecular condensation to obtain (Formula I-3) intermediates (condensation reagents are for example but not limited to HATU, HBTU, EDC.HCl, BOP), followed by acidic conditions (e.g. but not limited to CF 3 COOH, HCl) to remove the Boc protecting the free amine I-4.
  • condensation conditions such as but not limited to Zn / AcOH, Fe / NH 4 Cl / EtOH, Zn / NH 4 Cl / EtOH,
  • condensation reagents to perform intramolecular condensation to obtain (Formula I-3)
  • an amide condensation reagent (condensation reagents such as but not limited to HATU, HBTU, EDC.HCl, BOP) is used to condense the generated free amine with a suitable acid (formula III) to obtain an intermediate (formula I-5).
  • I-5 is treated with an alkynyl compound (formula II) containing R groups under Sonogashira coupling conditions to give the final product I-6.
  • the I-7 compound was prepared according to the same procedure as in Scheme IV, and the I-7 was treated with an alkynyl compound (Formula II) containing R groups under Sonogashira coupling conditions to obtain the intermediate formula I-11, followed by acidic conditions (For example, but not limited to CF 3 COOH, HCl) Deprotection of Boc gives free amine I-12. Furthermore, using an amide condensation reagent (condensation reagents such as but not limited to HATU, HBTU, EDC.HCl, BOP), the resulting free amine I-12 is condensed with a suitable acid (formula III) to obtain the final product (formula I-10 ).
  • an alkynyl compound (Formula II) containing R groups under Sonogashira coupling conditions to obtain the intermediate formula I-11, followed by acidic conditions (For example, but not limited to CF 3 COOH, HCl)
  • Boc Deprotection of Boc gives free amine I-12.
  • the Boc-L-cysteine is reacted with a suitably substituted 1-fluoro-2-nitrobenzene with a base to obtain I-13, and then the nitro group is reduced to the amine I-14 (reduction conditions such as but not limited to Zn / AcOH, Fe / NH 4 Cl / EtOH, Zn / NH 4 Cl / EtOH, and intramolecular condensation using condensation reagents to obtain intermediate formula I-15 (condensation reagents are, for example but not limited to HATU, HBTU, EDC.HCl, BOP), followed by acidic conditions (e.g. but not limited to CF 3 COOH, HCl) to remove the Boc protecting the free amine I-16.
  • condensation reagents are, for example but not limited to HATU, HBTU, EDC.HCl, BOP
  • acidic conditions e.g. but not limited to CF 3 COOH, HCl
  • the resulting free amine I-16 is condensed with a suitable acid (formula III) to obtain an intermediate (formula I-17 ).
  • the I-17 is treated with an alkynyl compound containing the R group (Formula II) under Sonogashira coupling conditions to give the final product I-18.
  • the I-19 compound was prepared according to the same procedure as in Scheme VII, and the I-19 was treated with an alkynyl compound (Formula II) containing R groups under Sonogashira coupling conditions to obtain the intermediate formula I-23, followed by acidic conditions (For example, but not limited to CF 3 COOH, HCl) Deprotection of Boc gives free amine I-24. Furthermore, using an amide condensation reagent (condensation reagents such as but not limited to HATU, HBTU, EDC.HCl, BOP), the resulting free amine I-24 is condensed with a suitable acid (formula III) to obtain the final product (formula I-22 ).
  • the resulting free amine I-28 is condensed with a suitable acid (formula III) to obtain an intermediate (formula I-29 ).
  • the I-29 is treated with an alkynyl compound (Formula II) containing R groups under Sonogashira coupling conditions to give the final product I-30.
  • the I-31 compound is prepared according to the same procedure as in Scheme X, and the I-31 is treated with an alkynyl compound (formula II) containing R groups under Sonogashira coupling conditions to obtain an intermediate formula I-35, followed by acidic conditions (For example, but not limited to CF 3 COOH, HCl) Deprotection of Boc gives free amine I-36. Furthermore, using an amide condensation reagent (condensation reagents such as but not limited to HATU, HBTU, EDC.HCl, BOP), the resulting free amine I-36 is condensed with a suitable acid (formula III) to obtain the final product (formula I-34 ).
  • an amide condensation reagent condensation reagents such as but not limited to HATU, HBTU, EDC.HCl, BOP
  • the resulting free amine I-36 is condensed with a suitable acid (formula III) to obtain the final product (formula I-
  • the acid-mediated schmidt reaction with sodium azide or the Beckmann rearrangement reaction of the ketoxime formed after the reaction with NH 2 OH can convert the appropriately substituted tetralone to the appropriately substituted 1,3,4 , 5-tetrahydro-1-benzoazazepine-2-one (Formula I-37).
  • I-37 is converted to ⁇ -iodobenzene lactam (formula I-38), and then converted to ⁇ -azidobenzolactam with sodium azide, And then staudinge reduction with triphenylphosphine to produce ⁇ -aminobenzene lactam (formula I-39), after chiral resolution to obtain the key intermediate (formula I-40), then amide condensation reagent and suitable The condensation of the acid (formula III) gives the intermediate (formula I-41). Finally, treatment of I-41 with an alkynyl compound containing R groups (Formula II) under Sonogashira coupling conditions gives the final product I-42.
  • the I-39 compound was prepared according to the same procedure as in Scheme 12, the intermediate ⁇ -aminobenzene lactam (Formula I-39) was protected with Boc, and then chiral resolution was performed to obtain the intermediate (Formula I-43).
  • the compounds of formula I-43 methylated to give I-44, and then under acidic conditions (e.g. but not limited to CF 3 COOH, HCl) to remove the Boc protecting the free amine I-45.
  • the I-40 compound was prepared according to the same procedure as in Scheme 12, and the intermediate (Formula I-43) was obtained by reacting the intermediate (Formula I-40) with Boc anhydride. Then use the steps in Scheme 13 to make the final product I-47.
  • the I-44 compound is prepared according to the same procedure as in Scheme XIII or XIV, and the I-44 is treated with an R group-containing alkynyl compound (Formula II) under Sonogashira coupling conditions to obtain the intermediate formula I-48, followed by Under acidic conditions (such as but not limited to CF 3 COOH, HCl), the Boc protection is removed to obtain the free amine I-49. Furthermore, using an amide condensation reagent (condensation reagents such as but not limited to HATU, HBTU, EDC.HCl, BOP), the resulting free amine I-49 is condensed with a suitable acid (formula III) to obtain the final product (formula I-47 ).
  • an R group-containing alkynyl compound Formula II
  • acidic conditions such as but not limited to CF 3 COOH, HCl
  • an amide condensation reagent condensation reagents such as but not limited to HATU, HBTU, EDC.HC
  • the Boc protection is removed to obtain the free amine I-54.
  • an amide condensation reagent condensation reagents such as but not limited to HATU, HBTU, EDC.HCl, BOP
  • the resulting free amine I-54 is condensed with a suitable acid (formula III) to obtain an intermediate (formula I-55 ).
  • I-55 is treated with an alkynyl compound (formula II) containing R groups under Sonogashira coupling conditions to give the final product I-56.
  • the compound I-52 was prepared according to the same procedure as in Scheme XVI, and the compound of formula I-52 was methylated to obtain I-57, which was then reacted with NIS to obtain intermediate formula I-58. Subsequently under acidic conditions (e.g. but not limited to CF 3 COOH, HCl) to remove the Boc protecting the free amine I-59. Furthermore, using an amide condensation reagent (condensation reagents such as but not limited to HATU, HBTU, EDC.HCl, BOP), the resulting free amine I-59 is condensed with a suitable acid (formula III) to obtain an intermediate (formula I-60 ). Finally, treatment of I-60 with R group-containing alkynyl compound (formula II) under Sonogashira coupling conditions gives the final product I-61.
  • acidic conditions e.g. but not limited to CF 3 COOH, HCl
  • an amide condensation reagent condensation reagents such
  • the optimal reaction conditions and reaction time for each individual step can vary depending on the specific reactants used and the substituents present in all reactants. Unless otherwise specified, solvents, temperatures, and other reaction conditions can be easily selected by those skilled in the art. Specific steps are provided in the Synthesis Examples section.
  • the reaction can be further processed in a conventional manner, for example by removing the solvent from the residue and further purified according to methods generally known in the art such as but not limited to crystallization, distillation, extraction, grinding and chromatography. Unless otherwise stated, the starting materials and reactants are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature.
  • Routine tests including appropriate adjustment of the reaction conditions, the reagents and sequence of the synthetic route, the protection of any chemical functional groups, which may not be compatible with the reaction conditions, and deprotection at appropriate points in the reaction sequence of the method, are included in this Within the scope of the invention.
  • Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples are found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (Third Edition) , John Wiley & Sons, NY (1999), which is incorporated by reference in its entirety.
  • the synthesis of the compounds of the present invention can be achieved by methods similar to those described in the synthesis schemes described above and in the specific examples.
  • the starting materials are not commercially available, they can be prepared by steps selected from the group consisting of standard organic chemistry techniques, techniques similar to the synthesis of known structural analogs, or techniques similar to the steps described in the above schemes or synthesis examples .
  • an optically active form of the compound of the present invention it can be obtained by performing one of the steps described herein using an optically active starting material (eg, prepared by asymmetric induction of an appropriate reaction step), or by using standard steps (eg, chromatographic separation , Recrystallization or enzymatic resolution) to obtain stereoisomeric mixtures of compounds or intermediates.
  • a pure geometric isomer of the compound of the present invention when required, it can be obtained by performing one of the above steps using the pure geometric isomer as the starting material, or by using standard procedures such as chromatographic separation to resolve the compound or intermediate Mixture of geometric isomers.
  • Figures 1 to 4 are model mice and normal mice to which the compounds ZB-R-53, ZB-R-54, ZB-R-55, and ZB-R-50 of the present application are administered in a hypothermic shock model. Temperature-time diagrams of blank control model mice and model mice administered with positive control compounds.
  • Figures 5 and 6 are the body weight-time graph and the disease activity index-time graph of normal mice, blank control group, positive control group administered with GSK and mice administered with compound ZB-R-51 of the present application, respectively.
  • 7 and 8 are the body weight-time graph and the disease activity index-time graph of normal mice, blank control group, positive control group administered with GSK, and mice administered with compound ZB-R-52 of the present application, respectively.
  • Fig. 9 is a comparison chart of colon length at the end of the experiment of normal mice, blank control group, positive control group administered with GSK and mice administered with compound ZB-R-52 of the present application.
  • Figures 10 to 14 are diagrams of normal mouse, blank control group, GSK positive control group, compound ZB-R-51 and compound ZB-R-52 of this application affecting the splenic T cell activation of UC mice.
  • 15 to 19 are diagrams of normal mice, blank control group, GSK positive control group, compound ZB-R-51 of the present application and compound ZB-R-52 of the present application affect T cell activation of mesenteric lymph nodes in UC mice.
  • N-Boc-L-cysteine (220 mg), M-1 (210 mg), NaHCO 3 (640 mg) was dissolved in ethanol (10 mL) and water (10 mL), and refluxed at 70 ° C. overnight under argon protection. The reaction solution was cooled to room temperature, 0.5 M / L hydrochloric acid was added to adjust the system to be acidic, extracted with ethyl acetate, and dried over anhydrous sodium sulfate to obtain compound M-2.
  • step 1
  • the M-12 obtained in the previous step was dissolved in 3 ml of DMSO, HATU (CAS: 148893-10-1, 120 mg) and N, N-diisopropylethylamine (130 mg) were added, and after 3 hours of reaction, ethyl acetate was added Ester and water extraction, the organic layer was collected, dried over anhydrous sodium sulfate, spin-dry the solvent and column chromatography to obtain M-13.
  • MM-1 (refer to patent: WO2014125444 for the synthesis of MM-1) in 3 ml of DMF. Add 30 mg of potassium carbonate and 24 mg of iodomethane. After 3 hours of reaction, add 15 ml of water. Precipitation, filtration and drying to obtain intermediate MM-2.
  • NN-2 40 mg was dissolved in 3 ml of dichloromethane, 1 ml of trifluoroacetic acid was added, and after 30 minutes of reaction, the solvent was spin-dried to obtain intermediate NN-3. It does not need to be purified and is directly invested in the next step.
  • Example 63 Test of cell viability (TNF ⁇ -induced necrotosis system of U937 cells
  • U937 cells were cultured in RPMI-1640 culture medium containing 10% fetal bovine serum (containing 100U / mL penicillin and 0.1g / L streptomycin) in a 37 ° C, 5% CO 2 saturated humidity incubator. Passage 3-4 times.
  • DMSO Dimethyl sulfoxide
  • the fluorescence value reflects the number of viable cells per well.
  • Compound inhibition rate (Fluorescence value of test compound sample-TNF ⁇ stimulation sample fluorescence value) / (Control well fluorescence value (Control)-TNF ⁇ stimulation sample fluorescence value) * 100, and then fit IC 50 .
  • GSK2982772 is a positive compound and is currently in a phase II clinical trial (J. Med. Chem. 2017, 60, 1247-1261).
  • ZB-R-53 0.11 ZB-R-54 0.10 ZB-R-55 ⁇ 0.5 ZB-R-68 0.2 ZB-R-76 0.54 ZB-R-78 0.35 ZB-R-80 0.31 ZB-R-81 0.29 ZB-R-82 0.30 ZB-R-84 0.19 ZB-R-85 1.09 ZB-R-87 0.2 ZB-R-89 1.7 ZB-R-20 ⁇ 0.5 ZB-R-24 ⁇ 1 ZB-R-25 ⁇ 2
  • TNF ⁇ -induced systemic inflammatory response syndrome (SIRS) model in C57BL / 6 mice TNF ⁇ -induced systemic inflammatory response syndrome (SIRS) model in C57BL / 6 mice
  • ml centrifuge tubes were purchased from Corning; commonly used surgical instruments (ophthalmic scissors, large forceps, small forceps, tissue scissors) and 1ml, 2ml, 10ml disposable plastic dispensers were purchased from Sinopharm Chemical Reagent Co., Ltd .; various specifications of pipettes Purchased from Eppendorf; various specifications of tips were purchased from Axygen and Sartoruris.
  • mice uses omnican insulinssyringes disposable sterile insulin syringes, product number: 9161635, needle outer diameter and length: 0.30 * 8mm; mouse tail vein syringe was purchased from Jinan Yiyan Technology Development Co., Ltd., model YLS -Q9G; laboratory animal anal temperature measuring instrument was purchased from Shanghai Alcote Biotechnology Co., Ltd., model ALC-ET06.
  • Recombinant Mouse mTNF ⁇ Use PBS to dissolve mTNF ⁇ into a 200 ⁇ g / ml stock solution of lyophilized powder, store in -20 °C refrigerator after dispensing. When in use, put the stock solution into the refrigerator at 4 °C overnight to dissolve and balance. On the day of modeling, dilute with PBS 5 times to 40 ⁇ g / ml, and mix gently by shaking.
  • the experimental animals are randomly grouped one day in advance according to body weight, 8 animals in each group.
  • Modeling starts 15 minutes after the administration, that is, PBS or mTNF ⁇ is injected into the tail vein and injected at the above dose.
  • Animal body temperature The anal temperature is measured every hour after modeling, and the protective effect of the compound on the decrease in body temperature can reflect its RIPK1 inhibitory activity.
  • GSK2982772 is a positive compound (J. Med. Chem. 2017, 60, 1247-1261).
  • the compounds ZB-R-53, ZB-R-54, ZB-R-55, and ZB-R-50 of the present application can all show better results than the positive control compound GSK2982772 in the low-temperature shock model.
  • the effect of better body temperature protection, that is, the degree of body temperature drop is lower.
  • the survival rate of the mice to which the compound of the present application was administered was 100% in the hypothermic shock model.
  • the compounds of the present application not only exhibit effective anti-systemic inflammatory response syndrome activity (relative to the blank control, ie vehicle), but also exhibit better activity relative to the positive control compound.
  • test animals were healthy adult male SD rats, with 3 rats in each group.
  • AUC last AUC from the time of administration to the last time point
  • AUC INF_obs AUC from the time of administration to the time point of theoretical extrapolation to infinity
  • the compound of the present invention has good pharmacokinetic absorption and has obvious pharmacokinetic advantages.
  • mice Female C57BL / 6 mice were randomly divided into normal control group, model group, GSK2982772 (GSK) treatment group, and compounds ZB-R-51 and ZB-R-52 (10mg / kg) with RIP1 inhibitory activity Group, 6 mice per group. Except for the mice in the normal control group, 3% DSS was added to the drinking water of the mice in the model group and the compound treatment group for 8 consecutive days to induce the intestinal inflammation model.
  • GSK2982772 and compounds ZB-R-51 and ZB-R-52 (10 mg / kg) were administered by intragastric administration from the day of mouse modeling to the end of the experiment.
  • each group of mice was weighed each day to detect fecal occult blood, and the disease activity of each mouse was scored according to Table 4 below.
  • Weight loss is divided into 5 levels (0, no weight loss or increase; 1, decrease 1-5%; 2, decrease 5-10%; 3, decrease 10-20%; 4, decrease more than 20%); feces Hardness is divided into 3 grades (0, normal; 2, soft stool; 4, loose stool); fecal occult blood is divided into 5 grades (0, negative; 1, +; 2, ++; 3, +++; 4, perianal bleeding ).
  • Figures 5 to 8 show the body weight and disease activity index versus time of normal mice, blank control group, control group and mice to which the compound of the present invention is administered.
  • intragastric administration of the active compounds ZB-R-51 and ZB-R-52 of the present invention can significantly improve the disease symptoms of DSS-induced inflammatory bowel disease mice, and improve weight loss and diarrhea , Bloody stools and other clinical symptoms.
  • mice colon tissue was taken, the length was measured, and the distal colon was intercepted and fixed in formalin. Paraffin-embedded sections were stained with H & E to make pathological sections.
  • 9 is a comparison chart of the colon length at the end of the experiment of normal mice, blank control group, GSK-administered positive control group and mice administered with the compounds ZB-R-51 and ZB-R-52 of the present application.
  • Figures 10 to 14 are diagrams of normal mouse, blank control group, GSK positive control group, compound ZB-R-51 and compound ZB-R-52 of this application affecting the splenic T cell activation of UC mice.
  • 15 to 19 are diagrams of normal mice, blank control group, GSK positive control group, compound ZB-R-51 of the present application and compound ZB-R-52 of the present application affect T cell activation of mesenteric lymph nodes in UC mice.
  • treatment with the compounds ZB-R-51 and ZB-R-52 of the present invention can significantly inhibit the shortening of the colon length caused by DSS-induced inflammation.
  • the compounds ZB-R-51 and ZB-R-52 compounds are significantly stronger than the positive compounds GSK2982772 (GSK) in the evaluation of multiple indicators.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

一种抑制RIP1激酶的杂环酰胺及其用途，特别涉及一种由通式（I）表示的化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物，包含该化合物的药物组合物及其制药用途。化合物对RIP1激酶介导的疾病或病症的治疗特别有效。

Description

抑制RIP1激酶的杂环酰胺及其用途 技术领域
本发明涉及一种杂环酰胺化合物及其用途，具体而言，本发明涉及一种抑制RIP1激酶的杂环酰胺及其用途。
背景技术
受体相互作用蛋白1(RIP1)激酶，最初被称为RIP，其是一种涉及先天免疫信号传导的TKL家族丝氨酸/苏氨酸蛋白激酶。RIP1激酶是一种包含蛋白的RHIM结构域，其具有N端激酶结构域和C端死亡结构域。RIP1死亡结构域介导与其他包含死亡结构域的蛋白的相互作用，所述蛋白包括Fas和TNFR-1，TRAIL-R1和TRAIL-R2和TRADD，而RHIM结构域对结合其他包含RHIM结构域的蛋白非常关键，所述蛋白如TRIF，DAI和RIP3，并通过这些相互作用实现其众多作用。RIP1是一种细胞信号传导的中心调节剂，其参与介导促存活和程序性细胞死亡通路二者，详细讨论如下。
RIP1在细胞信号传导中的作用已经在不同条件下进行了评估，但是在死亡受体TNFR1下游介导信号中能够获得最佳理解。通过TNF实现TNFS衔接，导致低聚反应，将多种蛋白，包括线性K63连接的多泛素化RIP1，TRAF2/5，TRADD和cIPAs，募集至受体的胞质尾区。依赖于RIP1的这种复合物作为支架蛋白(即非激酶依赖性)，称作复合物1，它通过激活NF-κB和MAP激酶通路为促存活信号传导提供了一个平台。另外，在促进RIP1脱泛素的条件下，TNF与其受体结合(通过例如A20和CYLD蛋白或cIAP抑制)，将导致受体内化和复合物II或DISC(死亡诱导信号复合物)的形成。DISC(包括RIP1、TRADD、FADD和半胱天冬酶8)的形成，导致半胱天冬酶8的激活，还以非RIP1激酶依赖性方式开始程序性凋亡细胞死亡。细胞凋亡很大程度上是一种静止形式的细胞死亡，其参与例如发育和细胞体内稳态等常规过程。
在DISC形成和RIP3表达，但是细胞凋亡被抑制的条件下(如FADD/半胱天冬酶8缺失、半胱天冬酶抑制或病毒感染)，就可能存在第三种RIP1激酶依赖性。现在，RIP3可以进入这个复合物，通过RIP1实现磷酸化，通过MLKL和PGAM5激活开始不依赖半胱天冬酶的程序性坏死细胞调亡。 与细胞凋亡相反，程序性坏死(不要与非程序性被动坏死混淆)导致从细胞释放危险相关分子模式(DAMP)。这些DAMP能够向周围细胞和组织提供一种“危险信号”，诱发促炎反应，包括炎性体激活，细胞因子生成和细胞募集反应。
通过使用RIP3基因敲除小鼠(其中RIP1介导的程序性坏死被完全阻断)和Necrotatin-1(一种具有较差的口服生物利用度的RIP1激酶活性的工具抑制剂)已经证明，RIP1激酶介导的程序性细胞死亡的调节异常与各种炎症有关。RIP3敲除小鼠已经显示对炎性肠病(包括溃疡性结肠炎和克罗恩氏病)，视网膜脱离诱导的感光细胞坏死，色素性视网膜炎，蛙皮素诱导的急性胰腺炎和败血症/全身炎症反应综合症(SIRS)具有保护作用。已经显示Necrotatin-1能有效缓解缺血性脑损伤，视网膜缺血/再灌注损伤，亨廷顿氏病，肾缺血再灌注损伤，顺铂诱导的肾损伤和创伤性脑损伤。至少部分由RIP1依赖性细胞凋亡、坏死或细胞因子生成调节的其他疾病或病症包括，血液和实体器官恶性肿瘤，细菌感染和病毒感染和戈谢病等
仍需要一种有效的、选择性的、小分子的RIP1激酶活性抑制剂，能够阻断RIP1依赖性细胞坏死、从而能够为与DAMP、细胞死亡和/或炎症有关的疾病或事件提供治疗效果。
发明内容
在一个方面，本发明提供通式(I)化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物：
Figure PCTCN2019109899-appb-000001
其中：
X为O、S、SO、
Figure PCTCN2019109899-appb-000002
NH、CO、CH 2、CF 2、CH(CH 3)、CH(OH)或N(CH 3)；
Y为C 1-C 2亚烷基(即CH 2或CH 2CH 2)；
环A为苯环、5-6元杂芳环、5-6元非芳香性杂环或
Figure PCTCN2019109899-appb-000003
所连接的羰基部分和L 1分别连接在环A的相间的位置上；
R A为H或C 1-C 4烷基；
L 1为C 3-C 6烷基、C 3-C 6烷氧基、卤代C 3-C 6烷氧基、C 3-C 6烯基、C 3-C 6烯基氧基、或者
Figure PCTCN2019109899-appb-000004
其中
L为O、S、NH、N(CH 3)、CH 2、CH 2CH 2、CH(CH 3)、CHF、CF 2、CH 2O、CH 2N(CH 3)、CH 2NH或CH(OH)；
环B为C 3-C 6环烷基、苯基、5-6元杂芳基或5-6元非芳香性杂环基；所述C 3-C 6环烷基、苯基、5-6元杂芳基或5-6元非芳香性杂环基各自独立地未被取代或者被一个或两个各自独立地选自下列的取代基所取代：卤素、C 1-C 4烷基、卤代C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、硝基和C 1-C 4烷基C(O)-；
R 2为H或CH 3；
环M独立地为C 6-C 10芳环或5-10元杂芳环；
R 1代表1-3个取代基，所述取代基各自独立地为H、卤素、-OH、-CN、-COOH、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 2-C 10烷氧基烷基、C 2-C 10卤代烷氧基烷基、C 1-C 6羟基烷基、-B(OH) 2、-S(O) n1R a、-N(R a) 2、-C(＝O)N(R a) 2、-NHC(＝O)R a、-NHC(＝O)OR a、-NHC(＝O)C(＝O)N(R a) 2、-NHC(＝O)C(＝O)OR a、-NHC(＝O)N(R a) 2、-NHC(＝O)NR aC(＝O)N(R a) 2、-NHC(＝O)NR aS(O) 2OR a、-NHC(＝O)NR aS(O) 2N(R a) 2、-NHC(＝S)N(R a) 2、-NHC(＝N-C≡N)NR a、-NHC(＝N-C≡N)SR a、-NHS(O) n1R a、M a、-(C 1-C 6亚烷基)-B(OH) 2、-(C 1-C 6亚烷基)-S(O) n1R a、-(C 1-C 6亚烷基)-N(R a) 2、-(C 1-C 6亚烷基)-C(＝O)N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝O)R a、-(C 1-C 6亚烷基)-NHC(＝O)OR a、-(C 1-C 6亚烷基)-NHC(＝O)C(＝O)N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝O)C(＝O)OR a、-(C 1-C 6亚烷基)-NHC(＝O)N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝O)NR aC(＝O)N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝O)NR aS(O) 2OR a、-(C 1-C 6亚烷基)-NHC(＝O)NR aS(O) 2N(R a) 2、 -(C 1-C 6亚烷基)-NHC(＝S)N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝N-C≡N)NR a、-(C 1-C 6亚烷基)-NHC(＝N-C≡N)SR a、-(C 1-C 6亚烷基)-NHS(O) n1R a、-(C 1-C 6亚烷基)-M a、-OM a、-SM a、-N(R a)M a；
R a在每次出现时各自独立地为氢、C 1-C 6烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 5-C 10环烯基；所述C 1-C 6烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 5-C 10环烯基各自独立地为未取代的或被1或2个氨基、羟基、C 1-C 4烷氧基、C 1-C 6烷基、C 3-C 10环烷基、或者CN取代；
M a在每次出现时各自独立地为C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基；所述C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基各自独立地为未取代或被一个或两个各自独立地选自下列的取代基所取代：卤素、C 1-C 4烷基、C 1-C 4烷氧基、-CN；
n1在每次出现时各自独立地为0、1或者2；
R各自独立地为氢、C 1-C 10烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基；所述C 1-C 10烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基各自独立地为未取代的或被1-4个M d取代；
M d在每次出现时各自独立地为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、C 1-C 6卤代烷基、-CN、NO 2、SCF 3、氧代、-OM e、-OC(O)M h、-OC(O)NM fM g、-SM e、-S(O) 2M e、-S(O) 2NM fM g、-C(O)M e、-C(O)-5-10元单环杂环、-C(O)-5-10元单环杂芳基、-C(O)OM e、-C(O)NM fM g、-NM fM g、-N(M e)C(O)M h、-N(M e)S(O) 2M h、-N(M e)C(O)OM h、-N(M e)C(O)NM fM g、-(C 1-C 6亚烷基)-OM e、-(C 1-C 6亚烷基)-OC(O)M h、-(C 1-C 6亚烷基)-OC(O)NM fM g、-(C 1-C 6亚烷基)-S(O) 2M e、-(C 1-C 6亚烷基)-S(O) 2NM fM g、-(C 1-C 6亚烷基)-C(O)M e、-(C 1-C 6亚烷基)-C(O)OM e、-(C 1-C 6亚烷基)-C(O)NM fM g、-(C 1-C 6亚烷基)-NM fM g、-(C 1-C 6亚烷基)-N(M e)C(O)M h、-(C 1-C 6亚烷基)-N(M e)S(O) 2M h、-(C 1-C 6亚烷基)-N(M e)C(O)OM h、-(C 1-C 6亚烷基)-N(M e)C(O)NM fM g、-(C 1-C 6亚烷基)-CN、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基；所述C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基各自独立地为未取代或被一个或两个各自独立地选自下列的取代基所取代：卤素、C 1-C 4烷基、C 1-C 4烷氧基、-CN；
M e、M f、M g和M h在每次出现时各自独立地为氢、C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 10环烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基；所述C 1-C 6烷基、C 3-C 10环烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基各自独立地为未取代或被一个或两个各自独立地选自下列的取代基所取代：卤素、羟基、C 1-C 4烷基、C 1-C 4烷氧基、-CN、-S(O) 2(C 1-C 4烷基)、-C(O)(C 1-C 4烷基)；
或者两个M d和与其相连的环原子一起形成一个3-8元的饱和或不饱和的环；
更具体而言，同碳上的两个M d可以和与其相连的环原子一起形成一个3-8元的饱和或者不饱和的环，从而形成螺环结构；
相邻碳上的两个M d可以和与其相连的环原子一起形成一个3-8元的饱和或者不饱和的环，从而形成并环结构；
相间碳上的两个M d可以和与其相连的环原子一起形成一个3-8元的饱和或者不饱和的环，从而形成桥环结构。
优选地，所述通式I的化合物为式Ia或者Ib所示的化合物：
Figure PCTCN2019109899-appb-000005
Z 1为N、CH、C(CH 3)、或者C(卤素)；
Z 2为N、或者CR 1；
Z 3为N、CH、C(CH 3)、或者C(卤素)；且Z 1、Z 2、Z 3不可同时为N；
Z 4为O、CR 1、S、N、或者NR 1；
Z 5为O、CR 1、S、N、或者NR 1；
A,L 1,X,Y,R,R A,R 1,R 2在出现时与上文中所述通式I中的定义相同；
优选地，所述通式I的化合物为式Ic、Id、Ie、或者If所示的化合物：
Figure PCTCN2019109899-appb-000006
Figure PCTCN2019109899-appb-000007
Z 1为N、CH、C(CH 3)、或者C(卤素)；
Z 2为N、或者CR 1；
Z 3为N、CH、C(CH 3)、或者C(卤素)；且Z 1、Z 2、Z 3不可同时为N；
Z 4为O、CR 1、S、N、或者NR 1；
Z 5为O、CR 1、S、N、或者NR 1；
A 1为C；A 4为C或者N；
并且A 2、A 3、和A 5各自独立地选自：CR A、O、S、N和NR A以形成呋喃基、噻吩基、异噁唑基、噁唑基、噻唑基、噁二唑基、吡咯基、吡唑基、咪唑基、三唑基、或四唑基环部分，其中至多一个R A不为氢；
A 6、A 7、A 8、和A 9各自独立地为CR A，其中至多一个R A不为氢；
或者A 6、A 7、A 8、和A 9之一为N，且其它A 6、A 7、A 8、和A 9为CH；
或者A 6、A 7、A 8、和A 9之一为N +-O -，且其它A 6、A 7、A 8、和A 9为CH；
L 1,X,Y,R,R A,R 1,R 2在出现时与上文中所述通式I中的定义相同。
在A 6至A 9中的所述N +-O -，是指N与环原子形成正鎓离子与O -离子的键合。
优选地，所述通式I所述的化合物为式Ig或Ih所示的化合物：
Figure PCTCN2019109899-appb-000008
R 1为H、卤素、-OH、-CN、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基；
X为O、S、CH 2、NH或者N(CH 3)；
A 1为C；A 4为C或者N；
并且A 2、A 3、和A 5各自独立地选自：CR A、O、S、N和NR A以形成呋喃基、噻吩基、异噁唑基、噁唑基、噻唑基、噁二唑基、吡咯基、吡唑基、咪唑基、三唑基、或四唑基环部分，其中至多一个R A不为氢；
L 1,R,R A在出现时与上文中所述通式I中的定义相同；
优选地，所述通式I所述的化合物为式Ii或Ij所示的化合物：
Figure PCTCN2019109899-appb-000009
R 1为H、卤素、-OH、-CN、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基；
X为O、S、CH 2、NH或者N(CH 3)；
A 6、A 7、A 8、和A 9各自独立地为CR A，其中至多一个R A不为氢；
或者A 6、A 7、A 8、和A 9之一为N，且其它A 6、A 7、A 8、和A 9为CH；
或者A 6、A 7、A 8、和A 9之一为N +-O -，且其它A 6、A 7、A 8、和A 9为CH；
L 1,R,R A在出现时与上文中所述通式I中的定义相同。
在A 6至A 9中的所述N +-O -，是指N与环原子形成正鎓离子与O -离子的键合。
优选地，所述通式I所述的化合物为式Ik或Il所示的化合物：
Figure PCTCN2019109899-appb-000010
R 1为H、F、Cl、CH 3、CH 2CH 3；
R为异噁唑基、噁唑基、噻唑基、噁二唑基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、C 3-C 6环烷基、
Figure PCTCN2019109899-appb-000011
它们各自独立地为未取代的或被1个F、Cl、甲基、乙基、异丙基或者环丙基取代。
优选地，所述通式I所述的化合物为式Im或In所示的化合物：
Figure PCTCN2019109899-appb-000012
R 1为H、F、Cl、CH 3、CH 2CH 3；
X为O、S、或者CH 2；
R为C 1-C 6烷基、C 6-C 10芳基、5-10元杂芳基、3-7元非芳香性杂环基、C 3-C 8环烷基、或C 5-C 8环烯基；所述C 1-C 6烷基、C 6-C 10芳基、5-10元杂芳基、3-7元非芳香性杂环基、C 3-C 8环烷基、或C 5-C 8环烯基各自独立地为未取代的或被1-4个M d取代；
M d选自F、Cl、甲基、乙基、丙基、丁基、三氟甲基、-(C 1-C 6亚烷基)-OH、异丙基、环丙基、羟基、甲氧基、氨基、甲氨基、二甲氨基、二乙氨基、C 6-C 10芳基、5-10元杂芳基、3-6元非芳香性杂环基；其中所述的C 6-C 10芳基、5-10元杂芳基、3-6元非芳香性杂环基、各自独立地为未取代或被一个或两个各自独立地选自下列的取代基所取代：卤素、C 1-C 4烷基、C 1-C 4烷氧基、-CN。
或者两个M d和与其相连的环原子一起形成一个3-8元的饱和或者不饱和的环。
优选地，所述通式I所述的化合物选自如下化合物：
Figure PCTCN2019109899-appb-000013
Figure PCTCN2019109899-appb-000014
Figure PCTCN2019109899-appb-000015
Figure PCTCN2019109899-appb-000016
Figure PCTCN2019109899-appb-000017
优选地，所述经同位素标记的化合物例如为氘取代的化合物。经同位素标记的化合物可以用于例如代谢检测等方面的应用。
在另一方面，本发明提供了一种药物组合物，其包含治疗有效量的选自根据本发明的的通式(I)化合物、其可药用盐、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记的化合物中的一种或多种，和任选地，可药用载体。
在另一方面，本发明中化合物对RIP1激酶介导的疾病或病症的治疗特别有效。这种RIP1介导的疾病或病症是通过激活RIP1激酶介导的疾病或病症；因此，RIP1激酶的抑制对这些疾病或病症的治疗有益。特别地，本 发明化合物可用于治疗可能至少部分由程序性坏死调节的疾病/病症，尤其是炎性肠病(包括克罗恩氏病、溃疡性结肠炎)、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、类风湿性关节炎、脊椎关节炎、痛风、SoJIA、系统性红斑狼疮、干燥综合症、全省性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪肝性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬发性胆管炎、肾炎、乳糜泻、自身免疫ITP、移植排斥、实体器官的缺血再灌注损伤、败血症、全身性炎症反应综合症、脑血管意外、心肌梗死、亨廷顿氏病、阿尔兹海默氏病、帕金森氏病、变应性疾病、哮喘、多发性硬化症、I型糖尿病、韦格纳肉芽肿、肺结节病、白塞氏病、白细胞介素-I转化酶相关的发热综合征、慢性阻塞性肺病、肿瘤坏死因子受体相关的周期性综合症和牙周炎。
根据本发明的另一方面，提供了用于制备本发明化合物的方法，其中，所述方法为选自以下的方案之一。
方案一：
Figure PCTCN2019109899-appb-000018
用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理芳基卤代物(式Ia-1，其中卤素为Cl、Br、或者I)制备(式I)化合物。通常，偶联反应在金属催化剂(包括但不限于金属钯催化剂和金属铜催化剂共同作用)和碱的存在下，并且在适当溶剂中在升高温度下(例如在约80℃至150℃)实现。反应可以通过微波辐射促进。所述金属钯催化剂包括但不限于双(三苯基膦)二氯化钯(II)、氯化烯丙基钯(II)二聚物、[1,1'-双(二苯基膦基)二茂铁]二氯化钯((dppf)PdCl 2)、醋酸钯(II)。所述金属铜催化剂包括但不限于碘化亚铜。可以使用的适当的碱的实例包括但不限于三乙胺、吡啶、二异丙基乙基胺、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)。适当溶剂的非限制性实例包括N,N-二甲基甲酰胺、二甲基乙酰胺、甲醇、乙醇、乙腈、二甲氧基乙烷、二甲基亚砜、二氧六环、四氢呋喃、乙二醇二甲醚、甲苯。
方案二：
Figure PCTCN2019109899-appb-000019
也可以用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理芳基卤代物(式Ib-1，其中卤素为Cl、Br、或者I)，偶联得到中间体(式Ib-2)后，随后在酸性条件下脱除Boc保护得到游离胺(式Ib-3)。进而使用酰胺缩合试剂，将生成的游离胺(式Ib-3)与合适的酸(式III)缩合，得到目标产物(式I)。
方案三：
Figure PCTCN2019109899-appb-000020
用碱将Boc-L-丝氨酸与合适取代的1-氟-2-硝基苯进行反应得到I-1，随后将硝基还原成胺I-2(还原条件例如但不限于Zn/AcOH,Fe/NH 4Cl/EtOH,Zn/NH 4Cl/EtOH,)，并使用缩合试剂进行分子内缩合得到(式I-3)中间体(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-4。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺与合适的酸(式III)缩合，得到中间体(式I-5)。最后，即用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-5得到终产物I-6。
方案四：
Figure PCTCN2019109899-appb-000021
或者，按照与方案三中相同的步骤制得I-3化合物，将式I-3化合物甲基化得到I-7,接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-8。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-8与合适的酸(式III)缩合，得到中间体(式I-9)。最后，用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-9得到终产物I-10。
方案五：
Figure PCTCN2019109899-appb-000022
按照与方案四中相同的步骤制得I-7化合物，用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-7得到中间体式I-11，接着 在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-12。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-12与合适的酸(式III)缩合，得到终产物(式I-10)。
方案六：
Figure PCTCN2019109899-appb-000023
用碱将Boc-L-半胱氨酸与合适取代的1-氟-2-硝基苯进行反应得到I-13，随后将硝基还原成胺I-14(还原条件例如但不限于Zn/AcOH,Fe/NH 4Cl/EtOH,Zn/NH 4Cl/EtOH,)，并使用缩合试剂进行分子内缩合得到中间体式I-15(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-16。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-16与合适的酸(式III)缩合，得到中间体(式I-17)。最后，即用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-17得到终产物I-18。
方案七：
Figure PCTCN2019109899-appb-000024
按照与方案六中相同的步骤制得I-15化合物，将式I-15化合物甲基化得到I-19,接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-20。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-20与合适的酸(式III)缩合，得到中间体(式I-21)。最后，用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-21得到终产物I-22。
方案八：
Figure PCTCN2019109899-appb-000025
按照与方案七中相同的步骤制得I-19化合物，用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-19得到中间体式I-23，接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-24。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU, EDC.HCl,BOP)，将生成的游离胺I-24与合适的酸(式III)缩合，得到终产物(式I-22)。
方案九：
Figure PCTCN2019109899-appb-000026
用碱将3-氨基丙氨酸与合适取代的1-氟-2-硝基苯进行反应得到I-25，随后将硝基还原成胺I-26(还原条件例如但不限于Zn/AcOH,Fe/NH 4Cl/EtOH,Zn/NH 4Cl/EtOH,)，并使用缩合试剂进行分子内缩合得到中间体式I-27(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-28。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-28与合适的酸(式III)缩合，得到中间体(式I-29)。最后，即用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-29得到终产物I-30。
方案十：
Figure PCTCN2019109899-appb-000027
按照与方案九中相同的步骤制得I-27化合物，将式I-27化合物甲基化得到I-31,接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-32。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-32与合适的酸(式III)缩合，得到中间体(式I-33)。最后，用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-33得到终产物I-34。
方案十一：
Figure PCTCN2019109899-appb-000028
按照与方案十中相同的步骤制得I-31化合物，用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-31得到中间体式I-35，接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺 I-36。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-36与合适的酸(式III)缩合，得到终产物(式I-34)。
方案十二：
Figure PCTCN2019109899-appb-000029
通过与叠氮化钠进行酸介导的schmidt反应或通过与NH 2OH反应后形成的酮肟的Beckmann重排反应，可将合适取代的四氢萘酮转化为合适取代的1,3,4,5-四氢-1-苯并氮杂卓-2-酮(式I-37)。然后通过三甲基碘硅烷介导的碘化反应，将I-37转化成α-碘苯内酰胺(式I-38)，随后用叠氮化钠转化成α-叠氮基苯内酰胺，并接着用三苯基膦进行staudinge还原，生成α-氨基苯内酰胺(式I-39)，经过手性拆分得到关键中间体(式I-40)，然后可使用酰胺缩合试剂与合适的酸(式III)缩合得到中间体(式I-41)。最后，即用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-41得到终产物I-42。
方案十三：
Figure PCTCN2019109899-appb-000030
按照与方案十二中相同的步骤制得I-39化合物，中间体α-氨基苯内酰胺(式I-39)使用Boc保护后，再手性拆分得到中间体(式I-43)。将式I-43化合物甲基化得到I-44,接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-45。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-45与合适的酸(式III)缩合，得到中间体(式I-46)。最后，用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-46得到终产物I-47。
方案十四：
Figure PCTCN2019109899-appb-000031
按照与方案十二中相同的步骤制得I-40化合物，通过中间体(式I-40)与Boc酸酐反应获得中间体(式I-43)。然后再用方案十三中的步骤制得终产物I-47。
方案十五：
Figure PCTCN2019109899-appb-000032
按照与方案十三或十四中相同的步骤制得I-44化合物，用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-44得到中间体式I-48，接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-49。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-49与合适的酸(式III)缩合，得到终产物(式I-47)。
方案十六：
Figure PCTCN2019109899-appb-000033
用碱将Boc-L-半胱氨酸与合适取代的3-溴-2-硝基噻吩进行反应得到I-50，随后将硝基还原成胺I-51(还原条件例如但不限于Pd/C/THF,Zn/AcOH,Fe/NH 4Cl/EtOH,Zn/NH 4Cl/EtOH,)，并使用缩合试剂进行分子内缩合得到中间体式I-52(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，接着与NIS反应得到中间体式I-53。接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-54。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-54与合适的酸(式III)缩合，得到中间体(式I-55)。最后，即用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-55得到终产物I-56。
方案十七：
Figure PCTCN2019109899-appb-000034
按照与方案十六中相同的步骤制得I-52化合物，将式I-52化合物甲基化得到I-57,接着与NIS反应得到中间体式I-58。随后在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-59。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-59与合适的酸(式III)缩合，得到中间体(式I-60)。最后，用 含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-60得到终产物I-61。
方案十八：
Figure PCTCN2019109899-appb-000035
按照与方案十七中相同的步骤制得I-58化合物，用含有R基团的炔基化合物(式II)在Sonogashira偶联条件下处理I-58得到中间体式I-62，接着在酸性条件下(例如但不限于CF 3COOH、HCl)脱除Boc保护得到游离胺I-63。进而使用酰胺缩合试剂(缩合试剂为例如但不限于HATU,HBTU,EDC.HCl,BOP)，将生成的游离胺I-63与合适的酸(式III)缩合，得到终产物(式I-61)。
每一独立步骤的最佳反应条件和反应时间可以根据所用特定反应物和所有反应物中存在的取代基改变。除非另外规定，溶剂、温度和其他反应条件可以由本领域技术人员容易选择。具体步骤提供在合成实施例部分。反应可以常规方式进一步处理，例如通过从残留物除去溶剂并根据本领域通常已知的方法例如但不限于结晶、蒸馏、萃取、研磨和色谱进一步纯化。除非另外说明，起始原料和反应剂是可商业购买的或者可以由本领域技术人员从可购买的材料使用化学文献描述的方法制备。
常规试验，包括适当调节反应条件、合成路线的反应剂和顺序、任意化学官能团的保护、其可以不与反应条件相适应，和在该方法的反应顺序的适当点进行脱保护，均包括在本发明范围内。适当保护基和使用这样的适当保护基进行保护和脱保护不同取代基的方法是本领域技术人员熟知的；其实例发现在T.Greene and P.Wuts,Protecting Groups in Chemical Synthesis(第三版)，John Wiley&Sons,NY(1999)，其以整体并入本文作 为参考。本发明化合物的合成可以由类似于上文和具体实施例中描述的合成方案中描述的那些方法来实现。
起始材料如果不可从商业渠道购买，可以由选自下列的步骤制备：标准有机化学技术、类似于合成已知结构类似物的技术、或类似于上述方案或合成实施例部分描述的步骤的技术。当需要本发明化合物的光学活性形式时，其可以由进行本文所述步骤之一使用光学活性起始材料(例如通过适当反应步骤的不对称诱导制备)获得，或者通过使用标准步骤(例如色谱分离、重结晶或酶拆分)拆分化合物或中间体的立体异构体混合物获得。
类似地，当需要本发明化合物的纯几何异构体时，其可以由使用纯几何异构体作为起始材料进行上述步骤之一获得，或者通过使用标准步骤，例如色谱分离拆分化合物或中间体的几何异构体混合物获得。
附图说明
图1-图4分别为在低温休克模型中施用了本申请的化合物ZB-R-53、ZB-R-54、ZB-R-55、ZB-R-50的模型小鼠与正常小鼠、空白对照的模型小鼠、施用阳性对照化合物的模型小鼠的体温-时间图。
图5和图6分别为正常小鼠、空白对照组、施用GSK的阳性对照组和施用本申请化合物ZB-R-51的小鼠的体重-时间图，以及疾病活动指数-时间图。
图7和图8分别为正常小鼠、空白对照组、施用GSK的阳性对照组和施用本申请化合物ZB-R-52的小鼠的体重-时间图，以及疾病活动指数-时间图。
图9是正常小鼠、空白对照组、施用GSK的阳性对照组和施用本申请化合物ZB-R-52的小鼠的实验终点时结肠长度的对比图。
图10-图14分别是正常小鼠、空白对照组、GSK阳性对照组、本申请化合物ZB-R-51和本申请化合物ZB-R-52影响UC小鼠脾脏T细胞活化图。
图15-图19分别是正常小鼠、空白对照组、GSK阳性对照组、本申请化合物ZB-R-51和本申请化合物ZB-R-52影响UC小鼠肠系膜淋巴结T细胞活化图。
具体实施方式
为了示例性目的，可以使用下列实施例，以下实施例仅用于解释说明本发明的技术方案，并不意图将本发明限制为这些实施例。
实施例1:中间体M-8的制备
Figure PCTCN2019109899-appb-000036
步骤一：
将500毫克3-溴-4-甲基噻吩(CAS:30318-99-1)溶于0.7mL醋酸酐以及醋酸(5mL)的混合物中，冰浴冷却10分钟后，加入150微升的发烟硝酸，室温下反应4h。随后将反应液倒入冰水中，有固体析出，过滤得到中间体M-1。
步骤二：
将N-Boc-L-半胱氨酸(220mg)，M-1(210mg),NaHCO 3(640mg)，溶于乙醇(10mL)与水(10mL)中，氩气保护下70℃回流过夜。将反应液冷却至室温，加入0.5M/L的盐酸调节体系至酸性，用乙酸乙酯萃取，无水硫酸钠干燥，得到化合物M-2。
步骤三：
将M-2(200mg),10％Pd/C(200mg)溶于四氢呋喃(20mL)中,氢气置换三次，在常温常压下进行氢化，反应12小时后，硅藻土过滤掉10％Pd/C，得到M-3的四氢呋喃溶液。
步骤四：
将上步得到的M-3的四氢呋喃溶液中，加入190毫克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC.HCl)，50毫克1-羟基苯并三唑(HOBT)，以及200毫克N,N-二异丙基乙胺(DEPEA)，室温反应3-4小时，旋干溶剂直接柱层析分离得到30毫克中间体M-4。
步骤五：
将M-4(220mg)，碳酸铯(330mg)，碘甲烷(125mg)，溶于10毫升无水四氢呋喃中，室温反应2小时，旋干溶剂，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，旋干溶剂后得到M-5。 1H NMR(400MHz,CDCl 3)δ6.84(m,1H),5.55(d,J＝7.4Hz,1H),4.50(dd,J＝18.3,7.2Hz,1H),3.75(dd,J＝10.8,6.6Hz,1H),3.39(s,3H),2.99(t,J＝11.2Hz,1H),2.22(d,J＝1.0Hz,3H),1.39(s,9H).
步骤六：
将上步得到的M-5溶于3毫升4M HCl的1,4-二氧六环溶液中，反应30分钟后直接旋干溶剂得到M-6。
步骤七：
将M-6(27mg)溶于DMSO(1mL)中，加入35毫克酸-1(该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯，CAS:148893-10-1,56mg),N,N-二异丙基乙胺(DIPEA)(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，柱层析得到M-7。
步骤八：
将M-7(80mg)溶于1毫升醋酸与2.5毫升氯仿中，加入N-碘代丁二酰亚胺(NIS)(52mg)，室温下反应30分钟，加入水，二氯甲烷萃取，无水硫酸钠干燥，旋干后得到M-8。
实施例2:
Figure PCTCN2019109899-appb-000037
将M-8(30mg)，4-乙炔吡喃(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL乙醇和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-44。HPLC-MS:[M+H] +＝522.2.
实施例3:
Figure PCTCN2019109899-appb-000038
将M-8(30mg)，环丙乙炔(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL乙醇和0.5mL三乙胺中，在氩气保护下， 加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-45。HPLC-MS:[M+H] +＝478.2. 1H NMR(400MHz,MeOD)δ7.30(m,5H),4.82(dd,J＝11.5,6.3Hz,1H),4.17(s,2H),3.78(dd,J＝11.1,6.7Hz,1H),3.37(s,3H),3.28(t,J＝11.5Hz,1H),2.28(s,3H),1.57(m,1H),1.02–0.89(m,2H),0.83–0.76(m,2H).
实施例4:
Figure PCTCN2019109899-appb-000039
将M-8(30mg)，2-乙炔基吡啶(11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL乙醇和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-46。HPLC-MS:[M+H] +＝515.2. 1H NMR(400MHz,MeOD)δ8.58(d,J＝5.0Hz,1H),7.90(t,J＝7.8Hz,1H),7.67(d,J＝7.8Hz,1H),7.45(dd,J＝7.4,5.0Hz,1H),7.38–7.20(m,5H),4.90–4.83(m,1H),4.17(s,2H),3.82(dd,J＝11.2,6.4Hz,1H),3.43(s,3H),3.33(t,J＝11.4Hz,1H),2.47(s,3H).
实施例5:
Figure PCTCN2019109899-appb-000040
将M-8(30mg)，4-乙炔基吡啶(11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL乙醇和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-47。 1H NMR(400MHz,CDCl 3)δ8.58(d,J＝4.5Hz,2H),8.13(brs,1H),7.37(d,J＝4.5Hz,2H),7.25(m,5H),4.92(m,1H),4.14(s,2H),3.87(dd,J＝11.1,6.6Hz,1H),3.41(s,3H),3.13(t,J＝11.1Hz,1H),2.39(s,3H).HPLC-MS:[M+H] +＝515.2.
实施例6:
Figure PCTCN2019109899-appb-000041
将M-8(30mg)，3-乙炔基吡啶(11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL乙醇和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-42。HPLC-MS:[M+H] +＝515.2. 1H NMR(400MHz,MeOD)δ8.71(d,J＝1.6Hz,1H),8.54(dd,J＝5.0,1.3Hz,1H),7.99(d,J＝7.9Hz,1H),7.49(dd,J＝7.9,5.0Hz,1H),7.37–7.22(m,5H),4.88–4.82(m,1H),4.17(s,2H),3.81(dd,J＝11.3,6.6Hz,1H),3.42(s,3H),3.33(t,J＝11.4Hz,1H),2.43(s,3H).
实施例7:
Figure PCTCN2019109899-appb-000042
将M-8(30mg)，1-Boc-4-乙炔基哌啶(11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL乙醇和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，加入水和乙酸乙酯，萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发旋干溶剂得到中间体。随后往该中间体中再加入2mL 4M HCl的1,4-二氧六环溶液，反应30分钟后，真空旋转蒸发除去溶剂，直接HPLC分离得到化合物ZB-R-48。HPLC-MS:[M+H] +＝521.2.
实施例8:
Figure PCTCN2019109899-appb-000043
步骤1：
将M-5(80mg)溶于1毫升醋酸与2.5毫升氯仿中，加入N-碘代丁二酰亚胺(NIS)(65mg)，室温下反应30分钟，加入水，二氯甲烷萃取，无水硫酸钠干燥，旋干后得到M-9。
步骤2：
将M-9(20mg)，N-甲基-4-炔基吡唑(CAS:39806-89-8)(11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL乙醇和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，柱层析分离得到化合物M-10。 1H NMR(400MHz,CDCl 3)δ7.64(s,1H),7.57(s,1H),5.55(d,J＝7.8Hz,1H),4.52(dt,J＝11.3,7.0Hz,1H),3.92(s,3H),3.76(dd,J＝11.1,6.4Hz,1H),3.38(s,3H),3.00(t,J＝11.3Hz,1H),2.29(s,3H),1.39(s,9H).
步骤3：
将M-10(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-1(该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-39。 1H NMR(400MHz,CDCl 3)δ8.15(d,J＝8.0Hz,1H),7.64(s,1H),7.58(s,1H),7.29–7.19(m,5H),4.92(dt,J＝11.5,7.4Hz,1H),4.15(s,2H),3.92(s,3H),3.85(dd,J＝10.5,5.8Hz,1H),3.39(s,3H),3.10(t,J＝11.3Hz,1H),2.32(s,3H).HPLC-MS:[M+H] +＝518.2
实施例9:
Figure PCTCN2019109899-appb-000044
将M-10(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-2(该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-1。HPLC-MS:[M+H] +＝518.2.
实施例10:
Figure PCTCN2019109899-appb-000045
将M-10(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-3(该酸来自商业购买，或者该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-2。HPLC-MS:[M+H] +＝517.2.
实施例11:
Figure PCTCN2019109899-appb-000046
将M-10(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-4(该酸来自商业购买，或者该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-3.HPLC-MS:[M+H] +＝531.2.
实施例12:
Figure PCTCN2019109899-appb-000047
将M-10(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-5(该酸来自商业购买，或者该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-4.HPLC-MS:[M+H] +＝518.2.
实施例13:
Figure PCTCN2019109899-appb-000048
将M-10(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-6(该酸来自商业购买，或者该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-5.HPLC-MS:[M+H] +＝518.2.
实施例14:
Figure PCTCN2019109899-appb-000049
将M-10(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-7(该酸来自商业购买，或者该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-6.HPLC-MS:[M+H] +＝528.1.
实施例15:
Figure PCTCN2019109899-appb-000050
步骤一：
将60％的氢化钠(430mg)溶于DMF(10mL)中，随后往该溶液中滴加N-Boc-L-丝氨酸(CAS:3262-72-4)(1000mg)的DMF(5mL)溶液，反应10分钟后，往溶液中加入4-溴-1-氟-2-硝基苯(CAS:364-73-8)(1.06g)，继续反应3小时。加入0.5M/L的盐酸调节体系至弱酸性，用乙酸乙酯萃取，无水硫酸钠干燥，得到化合物M-11。
步骤二：
将M-11(100mg)溶于醋酸(2mL)中，加入80mg锌粉，反应3小时后，过滤掉固体，将滤液旋干，加入二氯甲烷和水萃取，收集有机层，无水硫酸钠干燥，旋干溶剂后得到M-12。该步不需要纯化，直接投下一步。
步骤三：
将上步得到的M-12溶于3毫升DMSO中，加入HATU(CAS:148893-10-1,120mg)和N,N-二异丙基乙胺(130mg)，反应3小时后，加入乙酸乙酯和水萃取，收集有机层，无水硫酸钠干燥，旋干溶剂后柱层析得到M-13.
步骤四：
将50毫克M-13溶于3毫升DMF中，加入30毫克碳酸钾以及24毫克碘甲烷，反应3小时后，加入15毫升水，有大量固体析出，过滤，烘干，得到中间体M-14。
步骤五：
将40毫克M-14溶于3毫升二氯甲烷中，加入1毫升三氟醋酸，反应30分钟后，旋干溶剂得到中间体M-15。其不需要纯化，直接投下一步。
步骤六：
往上步获得的M-15中加入DMSO(1mL)，随后加入27毫克酸-1(该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)， HATU(62mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，柱层析得到M-16。 1H NMR(400MHz,MeOD)δ7.61(d,J＝2.3Hz,1H),7.42(dd,J＝8.6,2.3Hz,1H),7.32–7.21(m,5H),7.13(d,J＝8.8Hz,1H),4.99(dd,J＝11.5,7.5Hz,1H),4.57(dd,J＝9.9,7.5Hz,1H),4.40(dd,J＝11.6,10Hz,1H),4.14(s,2H),3.37(s,3H).
实施例16:
Figure PCTCN2019109899-appb-000051
将M-16(25mg)，2-乙炔基吡啶(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-50。HPLC-MS:[M+H] +＝479.2. 1H NMR(400MHz,MeOD)δ8.64(m,1H),8.01(t,J＝8.0Hz,1H),7.82–7.73(m,2H),7.60-7.52(m,2H),7.36-7.24(m,6H),5.06(m,1H),4.65(dd,J＝10.5,7.6Hz,1H),4.50(t,J＝10.5Hz,1H),4.19(s,2H),3.46(s,3H).
实施例17:
Figure PCTCN2019109899-appb-000052
将M-16(25mg)，3-乙炔基吡啶(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-51。HPLC-MS:[M+H] +＝479.2. 1H NMR(400MHz,DMSO-d 6)δ14.41(brs,1H),8.77(s,1H),8.61(d,J＝3.6Hz,1H),8.45(brs,1H),8.04–7.97(m,1H),7.77(d,J＝1.9Hz,1H),7.52-7.47(m,2H),7.34-7.22(m,6H),4.87(dt,J＝11.4,7.8Hz,1H),4.65(t,J＝10.3Hz,1H),4.45(dd,J＝9.8,7.6Hz,1H),4.12(s,2H),3.34(s,3H).
实施例18:
Figure PCTCN2019109899-appb-000053
将M-16(25mg)，4-乙炔基吡啶(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-51。HPLC-MS:[M+H] +＝479.2. 1H NMR(400MHz,MeOD)δ8.60(d,J＝5.2Hz,2H),7.71(s,1H),7.60(d,J＝5.6Hz,2H),7.54(d,J＝8.0Hz,1H),7.38–7.23(m,6H),5.07(dd,J＝11.5,7.5Hz,1H),4.68-4.62(m,1H),4.52-4.46(m,1H),4.19(s,2H),3.46(s,3H).
实施例19:
Figure PCTCN2019109899-appb-000054
将M-16(25mg)，N-甲基-4-炔基吡唑(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-53。HPLC-MS:[M+H] +＝482.2. 1H NMR(400MHz,MeOD)δ7.86(s,1H),7.65(s,1H),7.54(d,J＝1.6Hz,1H),7.42–7.19(m,7H),5.05(dd,J＝11.6,7.4Hz,1H),4.66–4.59(m,1H),4.49–4.40(m,1H),4.18(s,2H),3.92(s,3H),3.43(s,3H).
实施例20:
Figure PCTCN2019109899-appb-000055
将M-16(25mg)，4-乙炔吡喃(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-54。HPLC-MS:[M+H] +＝486.2.
实施例21:
Figure PCTCN2019109899-appb-000056
将M-16(25mg)，环丙乙炔(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-55。HPLC-MS:[M+H] +＝442.2. 1H NMR(400MHz,MeOD)δ7.42(d,J＝1.7Hz,1H),7.37–7.24(m,6H),7.15(d,J＝8.3Hz,1H),5.01(dd,J＝11.2,7.6Hz,1H),4.63–4.56(m,1H),4.45–4.38(m,1H),4.18(s,2H),3.40(s,3H),1.48(m,1H),0.94-0.88(m,2H),0.79–0.73(m,2H).
实施例22:
Figure PCTCN2019109899-appb-000057
将M-16(25mg)，5-乙炔基-1-甲基-1H-咪唑(CAS：71759-92-7，10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-56。HPLC-MS:[M+H] +＝482.2. 1H NMR(400MHz,MeOD)δ7.75(s,1H),7.65(s,1H),7.48(d,J＝8.3Hz,1H),7.37–7.22(m,7H),5.06(dd,J＝11.6,7.6Hz,1H),4.68–4.60(m,1H),4.51–4.43(m,1H),4.19(s,2H),3.82(s,3H),3.45(s,3H).
实施例23:
Figure PCTCN2019109899-appb-000058
将M-16(25mg)，3-炔基咪唑[1,2-B]哒嗪(CAS：943320-61-4，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-57。HPLC-MS:[M+H] +＝519.2. 1H NMR(400MHz,MeOD)δ8.63(d,J ＝3.6Hz,1H),8.15–8.04(m,2H),7.73(s,1H),7.56(d,J＝8.1Hz,1H),7.40-7.22(m,7H),5.08(dd,J＝11.1,7.1Hz,1H),4.69-4.60(m,1H),4.48(t,J＝10.6Hz,1H),4.19(s,2H),3.47(s,3H).
实施例24:
Figure PCTCN2019109899-appb-000059
将M-16(25mg)，1-Boc-4-乙炔基哌啶(12mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，加入水和乙酸乙酯，萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发旋干溶剂得到中间体。随后往该中间体中再加入3mL 4M HCl的1,4-二氧六环溶液，反应30分钟后，真空旋转蒸发除去溶剂HPLC分离(流动相为乙腈与水(含0.1％的三氟醋酸))得到化合物ZB-R-58。 1H NMR(400MHz,MeOD)δ7.50(s,1H),7.39–7.18(m,7H),5.02(dd,J＝11.2,7.6Hz,1H),4.65–4.54(m,1H),4.46(t,J＝10.8Hz,1H),4.19(s,2H),3.47-3.38(m,5H),3.24–3.14(m,2H),3.13–3.04(m,1H),2.25–2.12(m,2H),2.02–1.89(m,2H).HPLC-MS:[M+H] +＝485.2.
实施例25:
Figure PCTCN2019109899-appb-000060
将M-16(25mg)，1-甲基-2-乙炔基-咪唑(CAS：37067-93-9，10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-7。HPLC-MS:[M+H] +＝482.2.
实施例26:
Figure PCTCN2019109899-appb-000061
将M-16(25mg)，3-乙炔基咪唑并[1,2-A]吡啶(CAS：943320-53-4，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-8。HPLC-MS:[M+H] +＝518.2.
实施例27:
Figure PCTCN2019109899-appb-000062
将M-16(25mg)，5-乙炔基-1-甲基-1H-吡唑(5-Ethynyl-1-methyl-1H-pyrazole,CAS：19762-15-3，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-9。HPLC-MS:[M+H] +＝482.2.
实施例28:
Figure PCTCN2019109899-appb-000063
将M-16(25mg)，3-乙炔基-1-甲基-1H-吡唑(3-Ethynyl-1-methyl-1H-pyrazole,CAS：61514-59-8，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-9。HPLC-MS:[M+H] +＝482.2.
实施例29:
Figure PCTCN2019109899-appb-000064
将M-16(25mg)，N-甲基炔丙基胺(CAS：35161-71-8，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二 甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-67。HPLC-MS:[M+H] +＝445.4.
1H NMR(400MHz,甲醇-d 4)δ7.59(d,J＝1.9Hz,1H),7.43(dd,J＝8.3,1.9Hz,1H),7.36–7.23(m,6H),5.01(dd,J＝11.5,7.3Hz,1H),4.59(dd,J＝9.8,7.3Hz,1H),4.48(dd,J＝11.5,9.8Hz,1H),4.17(s,3H),3.40(s,3H),2.83(s,3H).
实施例30:
Figure PCTCN2019109899-appb-000065
将M-16(25mg)，甲基丙炔基醚(CAS：627-41-8，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-68。HPLC-MS:[M+H] +＝446.2. 1H NMR(400MHz,甲醇-d 4)δ7.51(d,J＝1.9Hz,1H),7.36(dd,J＝8.3,1.9Hz,1H),7.34–7.21(m,5H),7.19(d,J＝8.3Hz,1H),5.01(dd,J＝11.5,7.4Hz,1H),4.59(dd,J＝9.9,7.4Hz,1H),4.42(dd,J＝11.5,9.9Hz,1H),4.32(s,2H),4.16(s,2H),3.43(s,3H),3.39(s,3H).
实施例31:
Figure PCTCN2019109899-appb-000066
将M-16(25mg)，3-甲基丁炔醇-3(CAS：115-19-5，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-76。HPLC-MS:[M+H] +＝460.15. 1H NMR(400MHz,甲醇-d 4)δ7.44(d,J＝1.8Hz,1H),7.33–7.19(m,6H),7.16(d,J＝8.3Hz,1H),4.99(dd,J＝11.5,7.4Hz,1H),4.57(dd,J＝9.9,7.4Hz,1H),4.40(dd,J＝11.5,9.9Hz,1H),4.14(s,2H),3.37(s,3H),1.56(s,6H).
实施例32:
Figure PCTCN2019109899-appb-000067
将M-16(25mg)，1-乙炔基环丁醇(CAS：98135-75-2，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-77。HPLC-MS:[M+H] +＝472.2. 1H NMR(400MHz,甲醇-d 4)δ7.49(d,J＝1.9Hz,1H),7.34(dd,J＝8.4,2.0Hz,1H),7.32–7.21(m,5H),7.19(d,J＝8.3Hz,1H),5.01(dd,J＝11.5,7.4Hz,1H),4.59(dd,J＝9.9,7.4Hz,1H),4.42(dd,J＝11.5,9.9Hz,1H),2.52-2.43(m,2H),2.36-2.25(m,2H),1.93–1.82(m,2H).
实施例33:
Figure PCTCN2019109899-appb-000068
将M-16(25mg)，NE-1(CAS：1352492-38-6，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-78。HPLC-MS:[M+H] +＝474.2. 1H NMR(400MHz,甲醇-d 4)δ7.53(t,J＝1.4Hz,1H),7.41–7.18(m,7H),5.01(dd,J＝11.5,7.4Hz,1H),4.88(d,J＝6.4Hz,2H),4.71(d,J＝6.4Hz,2H),4.59(dd,J＝9.9,7.4Hz,1H),4.43(dd,J＝11.5,9.9Hz,1H),4.15(s,2H),3.38(d,J＝1.0Hz,3H).
实施例34:
Figure PCTCN2019109899-appb-000069
将M-16(25mg)，1－乙炔基环己醇(CAS：78-27-3，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应 3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-79。HPLC-MS:[M+H] +＝500.2. 1H NMR(400MHz,甲醇-d 4)δ7.46(d,J＝1.8Hz,1H),7.35–7.20(m,6H),7.18(d,J＝8.3Hz,1H),5.00(dd,J＝11.6,7.5Hz,1H),4.58(dd,J＝9.9,7.4Hz,1H),4.41(dd,J＝11.5,9.9Hz,1H),4.15(s,2H),3.38(s,3H),2.03–1.53(m,10H).
实施例35:
Figure PCTCN2019109899-appb-000070
将M-16(25mg)，(R)-5-甲基异恶唑-3-丁炔-2-醇(CAS：1202771-72-9，13mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-80。HPLC-MS:[M+H] +＝527.3. 1H NMR(400MHz,甲醇-d 4)δ7.52(d,J＝1.8Hz,1H),7.35(dd,J＝8.4,2.0Hz,1H),7.32–7.20(m,5H),7.17(d,J＝8.3Hz,1H),6.31(s,1H),4.99(dd,J＝11.6,7.4Hz,1H),4.58(dd,J＝9.9,7.4Hz,1H),4.41(dd,J＝11.5,9.9Hz,1H),4.14(s,2H),3.37(s,3H),2.42(s,3H),1.87(s,3H).
实施例36:
Figure PCTCN2019109899-appb-000071
将M-16(25mg)，(S)-5-甲基异恶唑-3-丁炔-2-醇(CAS：1202771-70-7，13mg)，PdCl2(PPh3)2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-81。HPLC-MS:[M+H] +＝527.3. 1H NMR(400MHz,甲醇-d 4)δ7.53(t,J＝1.4Hz,1H),7.37(dt,J＝8.3,1.4Hz,1H),7.33–7.21(m,5H),7.19(d,J＝8.3Hz,1H),6.31(s,1H),5.00(dd,J＝11.5,7.4Hz,1H),4.59(dd,J＝9.9,7.4Hz,1H),4.42(dd,J＝11.5,9.9Hz,1H),4.15(s,2H),3.38(s,3H),2.43(s,3H),1.87(s,3H).
实施例37:
Figure PCTCN2019109899-appb-000072
将M-8(30mg)，5-乙炔基-1-甲基-1H-咪唑(CAS：71759-92-7，11mg)，双三苯基磷二氯化钯[PdCl 2(PPh 3) 2,CAS:13965-03-2,4.6mg[,碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-82.HPLC-MS:[M+H]+＝518.6. 1H NMR(400MHz,甲醇-d 4)δ7.76(s,1H),7.35–7.19(m,6H),4.84(dd,J＝11.6,6.6Hz,1H),4.14(s,2H),3.78(dd,J＝11.6,6.6Hz,1H),3.76(s,3H),3.39(s,3H),3.30(t,J＝11.6Hz,1H),2.37(s,3H).
实施例38:
Figure PCTCN2019109899-appb-000073
将M-8(30mg)，3-炔基咪唑[1,2-B]哒嗪(CAS：943320-61-4，11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-83.HPLC-MS:[M+H] +＝555.4. 1H NMR(400MHz,甲醇-d 4)δ8.61(d,J＝4.4Hz,1H),8.08(d,J＝10.7Hz,2H),7.39–7.19(m,6H),4.86(dd,J＝11.4,6.5Hz,1H),4.15(s,2H),3.80(dd,J＝11.4,6.5Hz,1H),3.41(s,3H),3.32(t,J＝11.4Hz,1H),2.42(s,3H).
实施例39:
Figure PCTCN2019109899-appb-000074
将M-8(30mg)，甲基丙炔基醚(CAS：627-41-8，11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-84.HPLC-MS:[M+H] +＝482.3. 1H NMR(400MHz,甲醇-d 4)δ7.34-7.20(m,5H),4.81(dd,J＝11.5,6.5Hz,1H),4.38(s,2H),4.15(s,2H),3.76(dd,J＝11.4,6.5Hz,1H),3.42(s,3H),3.37(s,3H),3.28(t,J＝11.5Hz,1H),2.32(s,3H).
实施例40:
Figure PCTCN2019109899-appb-000075
将M-8(30mg)，3-甲基丁炔醇-3(CAS：115-19-5，11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mLN,N-二甲基甲酰胺(DMF)和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-85.HPLC-MS:[M+H] +＝496.1. 1H NMR(400MHz,甲醇-d 4)δ7.34–7.20(m,5H),4.80(dd,J＝11.5,6.6Hz,1H),4.15(s,2H),3.76(dd,J＝11.5,6.6Hz,1H),3.36(s,3H),3.28(t,J＝11.5Hz,1H),2.31(s,3H),1.57(s,6H).
实施例41:
Figure PCTCN2019109899-appb-000076
将M-8(30mg)，1-乙炔基环丁炔醇(CAS：98135-75-2，11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mLN,N-二 甲基甲酰胺(DMF)和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-85.HPLC-MS:[M+H] +＝508.1. 1H NMR(400MHz,甲醇-d 4)δ7.34-7.20(m,5H),4.81(dd,J＝11.5,6.5Hz,1H),4.15(s,2H),3.76(dd,J＝11.5,6.5Hz,1H),3.37(s,3H),3.28(t,J＝11.5Hz,1H),2.47(qd,J＝7.8,6.2,4.5Hz,2H),2.39–2.28(m,5H),1.88(td,J＝9.1,4.6Hz,2H).
实施例42:
Figure PCTCN2019109899-appb-000077
将M-8(30mg)，NE-1(CAS：1352492-38-6，11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mLN,N-二甲基甲酰胺(DMF)和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-87.HPLC-MS:[M+H] +＝510.2. 1H NMR(400MHz,甲醇-d 4)δ7.34-7.20(m,5H),4.87(d,J＝6.5Hz,2H),4.81(dd,J＝11.4,6.4Hz,1H),4.72(d,J＝6.5Hz,2H),4.15(s,2H),3.77(dd,J＝11.4,6.4Hz,1H),3.38(s,3H),3.30(t,J＝11.4Hz,1H),2.35(s,3H).
实施例43:
Figure PCTCN2019109899-appb-000078
将M-8(30mg)，1－乙炔基环己醇(CAS：78-27-3，11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mLN,N-二甲基甲酰胺(DMF)和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-88. 1H NMR(400MHz,甲醇-d 4)δ7.35-7.20(m,5H),4.81(dd,J＝11.5,6.5Hz,1H),4.15(s,2H),3.76(dd,J＝11.5,6.4Hz,1H),3.37(s,3H),3.28(t,J＝11.5Hz,1H),2.32(s,3H),2.07–1.92(m,2H),1.83–1.53(m,8H).
实施例44:
Figure PCTCN2019109899-appb-000079
将M-8(30mg)，反应式中的炔烃(CAS：1202771-72-9，11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mLN,N-二甲基甲酰胺(DMF)和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-89.HPLC-MS:[M+H] +＝563.3. 1H NMR(400MHz,甲醇-d 4)δ7.35–7.18(m,5H),6.29(s,1H),4.80(dd,J＝11.6,6.6Hz,1H),4.14(s,2H),3.76(dd,J＝11.6,6.6Hz,1H),3.36(s,3H),3.28(t,J＝11.6Hz,1H),2.43(s,3H),2.32(s,3H),1.87(s,3H).
实施例45:
Figure PCTCN2019109899-appb-000080
将M-8(30mg)，图示中的炔烃(CAS：1202771-70-7，11mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mLN,N-二甲基甲酰胺(DMF)和0.5mL三乙胺中，在氩气保护下，加热至70℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-90.[M+H] +＝563.3. 1H NMR(400MHz,甲醇-d 4)δ7.35–7.18(m,5H),6.29(s,1H),4.80(dd,J＝11.6,6.6Hz,1H),4.14(s,2H),3.76(dd,J＝11.6,6.6Hz,1H),3.36(d,J＝0.9Hz,3H),3.28(d,J＝11.6Hz,1H),2.43(s,3H),2.32(s,3H),1.88(s,3H).
实施例46:
Figure PCTCN2019109899-appb-000081
将M-14(25mg)，3-乙炔基吡啶(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物M-30。[M+H] +＝394.1.
实施例47:
Figure PCTCN2019109899-appb-000082
将M-30(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-2(该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-20。HPLC-MS:[M+H] +＝479.1.
实施例48:
Figure PCTCN2019109899-appb-000083
将M-30(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-3(该酸来自商业购买，或者该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-21。HPLC-MS:[M+H] +＝478.2.
实施例49:
Figure PCTCN2019109899-appb-000084
将M-30(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-4(该酸来自商业购买，或者该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-22.HPLC-MS:[M+H] +＝492.2.
实施例50:
Figure PCTCN2019109899-appb-000085
将M-30(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-5(该酸来自商业购买，或者该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-23.HPLC-MS:[M+H] +＝479.2.
实施例51:
Figure PCTCN2019109899-appb-000086
将M-30(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-6(该酸来自商业购买，或者该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-24.HPLC-MS:[M+H] +＝479.2.
实施例52:
Figure PCTCN2019109899-appb-000087
将M-30(25mg)溶于2mL二氯甲烷和1mL三氟醋酸中，反应1小时后，旋干溶剂得到中间体胺。随后将该中间体溶于DMSO(1mL)中，加入35毫克酸-7(该酸来自商业购买，或者该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(56mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-25.HPLC-MS:[M+H] +＝489.1.
实施例53:
Figure PCTCN2019109899-appb-000088
步骤一：
将50毫克MM-1(MM-1的合成请参考专利：WO 2014125444)溶于3毫升DMF中，加入30毫克碳酸钾以及24毫克碘甲烷，反应3小时后，加入15毫升水，有大量固体析出，过滤，烘干，得到中间体MM-2。
步骤二：
将40毫克MM-2溶于3毫升二氯甲烷中，加入1毫升三氟醋酸，反应30分钟后，旋干溶剂得到中间体MM-3。其不需要纯化，直接投下一步。
步骤三：
往上步获得的MM-3中加入DMSO(1mL)，随后加入20毫克酸-1(该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(62mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，柱层析得到MM-4。HPLC-MS:[M+H] +＝454.1.
实施例54:
Figure PCTCN2019109899-appb-000089
步骤一：
将50毫克NN-1(NN-1的合成请参考专利：WO 2014125444)溶于3毫升DMF中，加入30毫克碳酸铯以及24毫克碘甲烷，反应3小时后，加入15毫升水，有大量固体析出，过滤，烘干，得到中间体NN-2。
步骤二：
将40毫克NN-2溶于3毫升二氯甲烷中，加入1毫升三氟醋酸，反应30分钟后，旋干溶剂得到中间体NN-3。其不需要纯化，直接投下一步。
步骤三：
往上步获得的NN-3中加入DMSO(1mL)，随后加入20毫克酸-1(该酸的制备请参考文献：CN 105121432 A,J.Med.Chem.2017,60,1247)，HATU(62mg),DIPEA(60mg)，反应过夜，加入水和乙酸乙酯萃取，收集有机层，无水硫酸钠干燥，柱层析得到NN-4。HPLC-MS:[M+H] +＝472.1.
实施例55:
Figure PCTCN2019109899-appb-000090
将MM-4(25mg)，3-乙炔基吡啶(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-26。HPLC-MS:[M+H] +＝477.2.
实施例56:
Figure PCTCN2019109899-appb-000091
将MM-4(25mg)，2-乙炔基吡啶(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-27。HPLC-MS:[M+H] +＝477.2.
实施例57:
Figure PCTCN2019109899-appb-000092
将MM-4(25mg)，4-乙炔基吡啶(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-28。HPLC-MS:[M+H] +＝477.2.
实施例58:
Figure PCTCN2019109899-appb-000093
将MM-4(25mg)，环丙乙炔(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-29。HPLC-MS:[M+H] +＝440.2.
实施例59:
Figure PCTCN2019109899-appb-000094
将NN-4(25mg)，3-乙炔基吡啶(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-30。HPLC-MS:[M+H] +＝495.2.
实施例60:
Figure PCTCN2019109899-appb-000095
将NN-4(25mg)，2-乙炔基吡啶(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-31。HPLC-MS:[M+H] +＝495.2.
实施例61:
Figure PCTCN2019109899-appb-000096
将NN-4(25mg)，4-乙炔基吡啶(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-32。HPLC-MS:[M+H] +＝495.2.
实施例62:
Figure PCTCN2019109899-appb-000097
将NN-4(25mg)，环丙乙炔(10mg)，PdCl 2(PPh 3) 2(CAS:13965-03-2,4.6mg),碘化亚铜(2.5mg)溶于2mL N,N-二甲基甲酰胺(DMF)和1mL三乙胺中，在氩气保护下，加热至85℃，反应3个小时后，冷却至室温，真空旋转蒸发除去溶剂，HPLC分离得到化合物ZB-R-32。HPLC-MS:[M+H] +＝458.2.
实施例63：细胞活性的测试(TNFα诱导U937细胞程序性坏死(necroptosis)体系
1.细胞培养:
用含10％胎牛血清的RPMI-1640培养液(含100U/mL青霉素及0.1g/L链霉素)，于37℃、5％CO 2的饱和湿度培养箱中培养U937细胞，每周换液传代3-4次。
2.实验仪器:电子天平(Mettler Toledo METTLER TOLEDO(AL104))，水浴锅(上海精宏实验设备有限公司，DKZ-2)，正置显微镜(德国Leica Microsystems)，生物安全柜(Heal Force HF Safe-1500)，4℃冰箱(美国Haier HYC360)，-30℃冰箱(日本松下mdf-u539-pc)，-80℃冰箱(美国thermo fisher scientific 906-ULTS)，培养箱(Forma 311 Thermo Forma)，纯水系统(美国Millipore公司)，流式细胞仪(BDFACS Calibur)，酶标仪(美国PE Envision)
3.实验试剂:RPMI-1640培养液、RPMI-1640培养液(无酚红)、
Figure PCTCN2019109899-appb-000098
Luminescent Cell Viability Assay(promega,G7572)、Human TNFα(Peprotech,300-01A)、Q-VD-Oph(Selleck，S7311)、FITC Annexin V Apoptosis Detection Kit(BD,556547)、Reactive Oxygen Species Assay Kit(碧云天，S0033)
4.实验方案：采用TNFα诱导U937细胞程序性坏死体系，筛选具有RIP1激酶抑制活性的化合物。
1)收集U937细胞，制备单细胞悬液，并计数。
2)于96孔板中铺细胞5*10 6个/孔。
3)溶解化合物：二甲基亚砜(DMSO)溶解化合物，成为5mM储备液。
4)稀释化合物：50nM起始，2.5倍稀释，7个浓度梯度。
5)设置细胞对照孔(Control)，刺激对照孔(TNFα与QVD联合诱导细胞程序性坏死)，其余加入不同浓度受试化合物与25μM Q-VD-Oph共孵育30分钟，后加入100ng/ml TNFα刺激，培养24小时。
6)培养结束加入100μl
Figure PCTCN2019109899-appb-000099
Luminescent试剂，震荡2分钟后在酶标仪上读取荧光值。
5.化合物抑制活性评价：荧光值反映每孔活细胞数目。化合物抑制率＝(受试化合物样品荧光值-TNFα刺激样品荧光值)/(对照孔荧光值(Control)-TNFα刺激样品荧光值)*100，进而拟合IC 50。
其中GSK2982772为阳性化合物，目前正处于II期临床试验中(J.Med.Chem.2017,60,1247-1261)。
表1
化合物 RIP1 IC 50(nM)
GSK2982772 2.30
ZB-R-39 0.17
ZB-R-42 0.32
ZB-R-44 4.08
ZB-R-45 8.13
ZB-R-46 5.39
ZB-R-47 0.39
ZB-R-50 0.26
ZB-R-51 <0.5
ZB-R-52 0.42
ZB-R-53 0.11
ZB-R-54 0.10
ZB-R-55 <0.5
ZB-R-68 0.2
ZB-R-76 0.54
ZB-R-78 0.35
ZB-R-80 0.31
ZB-R-81 0.29
ZB-R-82 0.30
ZB-R-84 0.19
ZB-R-85 1.09
ZB-R-87 0.2
ZB-R-89 1.7
ZB-R-20 <0.5
ZB-R-24 <1
ZB-R-25 <2
从上表1结果可以得知，部分化合物的细胞活性明显强于阳性化合物GSK2982772。其中数个化合物的细胞活性已经强于阳性化合物GSK2982772十倍以上。
实施例64：
TNFα诱导C57BL/6小鼠全身炎症反应综合征(SIRS)模型
1.试验动物：
来源，种系，品系：C57BL/6纯系小鼠，雌性，18-20克，购自上海灵畅生物科技有限公司，许可证号：SCXK(沪)2013-0018号。动物饲养于上海药物研究所2楼SPF动物房，实验动物使用许可证号：SYXK(沪)2013-0049号，动物至少饲养一周后使用。温度22±1℃，湿度55±5％，12小时光暗循环。饲料和水均在消毒后由动物自由摄取。所有实验均严格按照实验动物有关条例进行。
2.试验试剂及材料：
1)Recombinant Mouse mTNFα购自上海近岸生物公司。
2)实验材料：1.5ml离心管购自Axygen公司、15ml及50
ml离心管购自Corning公司；常用手术器械(眼科剪、大镊子、小镊子、组织剪)及1ml、2ml、10ml一次性塑料加液器购自国药化学试剂有限公 司；各种规格移液器购自Eppendorf公司；各种规格吸头购自Axygen及Sartoruris公司。
3)实验器材：注射器采用omnican insulin syringes一次性使用无菌胰岛素注射器，产品编号：9161635，针管外径和长度：0.30*8mm；小鼠尾静脉注射器购自济南益延科技发展有限公司，型号YLS-Q9G；实验动物肛温测量仪购自上海奥尔科特生物技术有限公司，型号ALC-ET06。
3.试剂及化合物配制方法：
1)Recombinant Mouse mTNFα：用PBS将冻干粉将mTNFα溶解为200μg/ml的stock溶液，分装后储存在-20℃冰箱。使用时将stock溶液放入4℃冰箱过夜，溶解平衡。造模当天用PBS5倍稀释为40μg/ml，轻震混匀。
2)化合物配制：阳性对照药物及受试化合物均采用0.2％HPMC混悬的方式，经超声后形成均一的混悬液。药物浓度依照体外实验结果及药代属性综合确定。
4.实验方案：
1)模型介绍：该模型通过尾静脉注射TNFα，造成小鼠全身系统性炎症反应并伴随低温休克。项目研究对象RIP1蛋白属于TNF受体下游蛋白，在炎症反应中发挥关键作用。因此选取尾静脉注射TNFα模型作为RIP1抑制剂动物水平筛选的经典模型。
2)实验过程：
a)实验动物提前一天依据体重随机分组，每组8只。
b)实验当天将mTNFα和无菌PBS按照上述方式稀释后，抽吸至胰岛素注射器中，125μl/支，即5μg/mice。
c)造模前15min给药，采用灌胃给药方式，0.2ml/只。
d)给药后15分钟开始造模，即尾静脉注射PBS或mTNFα，按照上述剂量注射。
e)造模结束后，每隔1h测量一次肛温，并检测存活率。
5.检测指标：
1)动物体温：造模后每小时测量肛温一次，化合物对体温下降的保护作用可反应其RIPK1抑制活性。
2)死亡率：动物体温下降至26℃以下时会死亡，检测死亡率也是评价化合物对动物低温休克反应保护作用的指标。
其中GSK2982772为阳性化合物(J.Med.Chem.2017,60,1247-1261)。
对ZB-R-53、ZB-R-54、ZB-R-55、ZB-R-50和阳性对照化合物GSK2982772的上述动物体温和死亡率的实验结果示于图1-图4和下表2中。
如图1-图4所示，本申请的化合物ZB-R-53、ZB-R-54、ZB-R-55、ZB-R-50在低温休克模型中均能表现出比阳性对照化合物GSK2982772更好的体温保护的效果，即，体温下降的程度更低。
表2
小鼠类型 存活率
正常小鼠 100％
未给药的模型小鼠 50％
GSK2982772治疗的小鼠 100％
ZB-R-53治疗的小鼠 100％
ZB-R-54治疗的小鼠 100％
ZB-R-55治疗的小鼠 100％
ZB-R-50治疗的小鼠 100％
如表2所示，施用了本申请的化合物的小鼠在低温休克模型中生存率为100％。
因此，本申请的化合物不但体现了有效的抗全身炎症反应综合征的活性(相对于空白对照，即载体)，而且相对于阳性对照化合物也体现了更好的活性。
实施例65：
大鼠口服药代动力学研究
1、以健康雄性SD大鼠为受试动物，灌胃给予ZB-R-39,ZB-R-50,ZB-R-51,ZB-R-52,ZB-R-53,ZB-R-54,ZB-R-55(3mg/kg)，应用LC/MS/MS法测定给药后不同时间点大鼠血浆中的药物浓度。研究本发明的化合物在大鼠体内的药代动力学行为，评价其药动学特性。
2、试验动物为健康成年雄性SD大鼠，每组3只。
3、药物配制：化合物ZB-R-39,ZB-R-50,ZB-R-51,ZB-R-52,ZB-R-53,ZB-R-54,ZB-R-55分别溶于DMSO/0.5％HPMC(5/95,v/v)配制，涡旋振荡，超声，使固体物质分散均匀，得淡白色混悬液。
4、操作：大鼠灌胃(3mg/kg)分别给药ZB-R-39,ZB-R-50,ZB-R-51,ZB-R-52,ZB-R-53,ZB-R-54,ZB-R-55，于给药后0.25，0.5，1，2，4，8，24小时分别经股静脉取血45μL，置肝素化的离心管中离心5min，分离血浆 样品分析。采用液相色谱串联质谱(LC-MS/MS)法测定不同化合物灌胃给药后大鼠血浆的待测化合物含量。
本发明化合物的药代动力学参数如下表3所示：
表3
Figure PCTCN2019109899-appb-000100
AUC last：从给药时间开始到最后一个时间点的这段时间的AUC
AUC INF_obs:从给药时间开始到理论外推无穷远的时间点的这段时间的AUC
如表3所示，本发明的化合物药代吸收良好，具有明显的药代动力学优势。
实施例66：
[一]DSS诱导溃疡性结肠炎小鼠模型建立及药效学评价
1.雌性C57BL/6小鼠随机分为正常对照组、模型组、GSK2982772(GSK)治疗组、以及具有RIP1抑制活性作用的化合物ZB-R-51与ZB-R-52(10mg/kg)治疗组，每组6只小鼠。除正常对照组的小鼠以外，其他各组包括模型组、化合物治疗组小鼠的饮用水中均加入了3％DSS连续8天进行肠道炎症模型的诱导造模。
2.自小鼠诱导造模日开始至实验终点，各治疗组分别给予GSK2982772和化合物ZB-R-51与ZB-R-52(10mg/kg)灌胃给药进行治疗干预。
3.疾病活动指数评价
实验期间对各组小鼠进行每天称取小鼠重量，检测粪便隐血，根据如下表4对每只小鼠疾病活动进行评分。
表4疾病活动指数(DAI)评分表
Figure PCTCN2019109899-appb-000101
表4.体重减轻分成5级(0，体重没有下降或上升；1，下降1-5％；2，下降5-10％；3，下降10-20％；4，下降超过20％)；粪便硬度分成3级(0，正常；2，软便；4，稀便)；粪便隐血分成5级(0，阴性；1，+；2，++；3，+++；4，肛周出血)。
图5至图8示出了正常小鼠、空白对照组、对照组以及施用本发明化合物的小鼠的体重和疾病活动指数对时间的曲线图。从图5至图8可以看出，给予本发明的活性化合物ZB-R-51和ZB-R-52灌胃治疗可明显改善DSS诱导的炎症性肠病小鼠疾病症状，改善体重减轻、腹泻、便血等临床症状。
[二]小鼠结肠组织整体及微观病理学变化
实验终点取小鼠结肠组织，量取长度，截取远端结肠固定于福尔马林中，石蜡包埋切片、H&E染色制作病理学切片。
图9是正常小鼠、空白对照组、施用GSK的阳性对照组和施用本申请化合物ZB-R-51和ZB-R-52的小鼠的实验终点时结肠长度的对比图。
图10-图14分别是正常小鼠、空白对照组、GSK阳性对照组、本申请化合物ZB-R-51和本申请化合物ZB-R-52影响UC小鼠脾脏T细胞活化图。
图15-图19分别是正常小鼠、空白对照组、GSK阳性对照组、本申请化合物ZB-R-51和本申请化合物ZB-R-52影响UC小鼠肠系膜淋巴结T细胞活化图。
从图9可以看出，给予本发明化合物ZB-R-51和ZB-R-52治疗可显著抑制由DSS诱导炎症所致的结肠长度缩短。
从图10至图19可以看出，化合物ZB-R-51和ZB-R-52化合物在多个指标的评价上要明显强于阳性化合物GSK2982772(GSK).
因此，上述代表性化合物ZB-R-51和ZB-R-52在硫酸葡聚糖(DSS)诱导的炎症性肠病小鼠动物模型中的实验研究结果表明：灌胃给药能够有效改 善实验动物的体重下降、腹泻、便血等结肠炎的临床症状，减轻结肠组织的病理学损伤，药效药理学研究证实该类型化合物具有良好的抗炎免疫抑制活性和较高的安全性，在临床治疗和辅助治疗炎症性肠病方面具有良好的应用前景。

Claims (10)

  1. 一种由通式I表示的化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物：
    Figure PCTCN2019109899-appb-100001
    其中：
    X为O、S、SO、
    Figure PCTCN2019109899-appb-100002
    NH、CO、CH 2、CF 2、CH(CH 3)、CH(OH)或N(CH 3)；
    Y为C 1-C 2亚烷基；
    环A为苯环、5-6元杂芳环、5-6元非芳香性杂环或
    Figure PCTCN2019109899-appb-100003
    所连接的羰基部分和L 1分别连接在环A的相间的位置上；
    R A为H或C 1-C 4烷基；
    L 1为C 3-C 6烷基、C 3-C 6烷氧基、卤代C 3-C 6烷氧基、C 3-C 6烯基、C 3-C 6烯基氧基、或者
    Figure PCTCN2019109899-appb-100004
    其中
    L为O、S、NH、N(CH 3)、CH 2、CH 2CH 2、CH(CH 3)、CHF、CF 2、CH 2O、CH 2N(CH 3)、CH 2NH或CH(OH)；
    环B为C 3-C 6环烷基、苯基、5-6元杂芳基或5-6元非芳香性杂环基；其中所述C 3-C 6环烷基、苯基、5-6元杂芳基或5-6元非芳香性杂环基未被取代或者被一个或两个各自独立地选自下列的取代基所取代：卤素、C 1-C 4烷基、卤代C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、硝基和C 1-C 4烷基C(O)-；
    R 2为H或CH 3；
    环M独立地为C 6-C 10芳环或5-10元杂芳环；
    R 1代表1-3个取代基，所述取代基各自独立地为H、卤素、-OH、-CN、-COOH、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 2-C 10烷氧基烷基、C 2-C 10卤代烷氧基烷基、C 1-C 6羟基烷基、-B(OH) 2、-S(O) n1R a、-N(R a) 2、-C(＝O)N(R a) 2、-NHC(＝O)R a、-NHC(＝O)OR a、-NHC(＝O)C(＝O)N(R a) 2、-NHC(＝O)C(＝O)OR a、-NHC(＝O)N(R a) 2、-NHC(＝O)NR aC(＝O)N(R a) 2、-NHC(＝O)NR aS(O) 2OR a、-NHC(＝O)NR aS(O) 2N(R a) 2、-NHC(＝S)N(R a) 2、-NHC(＝N-C≡N)NR a、-NHC(＝N-C≡N)SR a、-NHS(O) n1R a、M a、-(C 1-C 6亚烷基)-B(OH) 2、-(C 1-C 6亚烷基)-S(O) n1R a、-(C 1-C 6亚烷基)-N(R a) 2、-(C 1-C 6亚烷基)-C(＝O)N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝O)R a、-(C 1-C 6亚烷基)-NHC(＝O)OR a、-(C 1-C 6亚烷基)-NHC(＝O)C(＝O)N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝O)C(＝O)OR a、-(C 1-C 6亚烷基)-NHC(＝O)N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝O)NR aC(＝O)N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝O)NR aS(O) 2OR a、-(C 1-C 6亚烷基)-NHC(＝O)NR aS(O) 2N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝S)N(R a) 2、-(C 1-C 6亚烷基)-NHC(＝N-C≡N)NR a、-(C 1-C 6亚烷基)-NHC(＝N-C≡N)SR a、-(C 1-C 6亚烷基)-NHS(O) n1R a、-(C 1-C 6亚烷基)-M a、-OM a、-SM a、-N(R a)M a；
    R a在每次出现时各自独立地为氢、C 1-C 6烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 5-C 10环烯基；所述C 1-C 6烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基或C 5-C 10环烯基各自独立地为未取代的或被1或2个氨基、羟基、C 1-C 4烷氧基、C 1-C 6烷基、C 3-C 10环烷基、或者CN取代；
    M a在每次出现时各自独立地为C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基；所述C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基各自独立地为未取代或被一个或两个各自独立地选自下列的取代基所取代：卤素、C 1-C 4烷基、C 1-C 4烷氧基、-CN；
    n1在每次出现时各自独立地为0、1或者2；
    R各自独立地为氢、C 1-C 10烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基；所述C 1-C 10烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基各自独立地为未取代的或被1-4个M d取代；
    M d在每次出现时各自独立地为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、C 1-C 6卤代烷基、-CN、NO 2、SCF 3、氧代、-OM e、-OC(O)M h、-OC(O)NM fM g、-SM e、-S(O) 2M e、-S(O) 2NM fM g、-C(O)M e、-C(O)-5-10元单环杂环、-C(O)-5-10元单环杂芳基、-C(O)OM e、-C(O)NM fM g、-NM fM g、-N(M e)C(O)M h、-N(M e)S(O) 2M h、-N(M e)C(O)OM h、-N(M e)C(O)NM fM g、-(C 1-C 6亚烷基)-OM e、-(C 1-C 6亚烷基)-OC(O)M h、-(C 1-C 6亚烷基)-OC(O)NM fM g、-(C 1-C 6亚烷基)-S(O) 2M e、-(C 1-C 6亚烷基)-S(O) 2NM fM g、-(C 1-C 6亚烷基)-C(O)M e、-(C 1-C 6亚烷基)-C(O)OM e、-(C 1-C 6亚烷基)-C(O)NM fM g、-(C 1-C 6亚烷基)-NM fM g、-(C 1-C 6亚烷基)-N(M e)C(O)M h、-(C 1-C 6亚烷基)-N(M e)S(O) 2M h、-(C 1-C 6亚烷基)-N(M e)C(O)OM h、-(C 1-C 6亚烷基)-N(M e)C(O)NM fM g、-(C 1-C 6亚烷基)-CN、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基；所述C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基、C 3-C 10环烷基、或C 3-C 10环烯基各自独立地为未取代或被一个或两个各自独立地选自下列的取代基所取代：卤素、C 1-C 4烷基、C 1-C 4烷氧基、-CN；
    M e、M f、M g和M h在每次出现时各自独立地为氢、C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 10环烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基；所述C 1-C 6烷基、C 3-C 10环烷基、C 6-C 10芳基、5-10元杂芳基、3-10元非芳香性杂环基各自独立地为未取代或被一个或两个各自独立地选自下列的取代基所取代：卤素、羟基、C 1-C 4烷基、C 1-C 4烷氧基、-CN、-S(O) 2(C 1-C 4烷基)、-C(O)(C 1-C 4烷基)；
    或者两个M d和与其相连的环原子一起形成一个3-8元的饱和或者不饱和的环。
  2. 根据权利要求1所述的化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物，其中，所述通式I的化合物选自式Ia或Ib所示的化合物：
    Figure PCTCN2019109899-appb-100005
    Z 1为N、CH、C(CH 3)、或者C(卤素)；
    Z 2为N或者CR 1；
    Z 3为N、CH、C(CH 3)、或者C(卤素)；且Z 1、Z 2、Z 3不可同时为N；
    Z 4为O、CR 1、S、N、或者NR 1；
    Z 5为O、CR 1、S、N、或者NR 1；
    A,L 1,X,Y,R,R A,R 1,R 2与权利要求1中所述通式I中的定义相同。
  3. 根据权利要求1所述的化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物，其中，所述通式I的化合物选自式Ic、Id、Ie、或者If所示的化合物：
    Figure PCTCN2019109899-appb-100006
    Z 1为N、CH、C(CH 3)、或者C(卤素)；
    Z 2为N、或者CR 1；
    Z 3为N、CH、C(CH 3)、或者C(卤素)；且Z 1、Z 2、Z 3不可同时为N；
    Z 4为O、CR 1、S、N、或者NR 1；
    Z 5为O、CR 1、S、N、或者NR 1；
    A 1为C；A 4为C或者N；
    并且A 2、A 3、和A 5各自独立地选自：CR A、O、S、N和NR A以形成呋喃基、噻吩基、异噁唑基、噁唑基、噻唑基、噁二唑基、吡咯基、吡唑基、咪唑基、三唑基、或四唑基环部分，其中至多一个R A不为氢；
    A 6、A 7、A 8、和A 9各自独立地为CR A，其中至多一个R A不为氢；
    或者A 6、A 7、A 8、和A 9之一为N，且其它A 6、A 7、A 8、和A 9为CH；
    或者A 6、A 7、A 8、和A 9之一为N +-O -，且其它A 6、A 7、A 8、和A 9为CH；
    L 1,X,Y,R,R A,R 1,R 2与权利要求1中通式I中的定义相同。
  4. 根据权利要求1所述的化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物，其中，所述通式I的化合物选自式Ig或Ih所示的化合物：
    Figure PCTCN2019109899-appb-100007
    R 1为H、卤素、-OH、-CN、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基；
    X为O、S、CH 2、NH或者N(CH 3)；
    A 1为C；A 4为C或者N；
    并且A 2、A 3、和A 5各自独立地选自：CR A、O、S、N和NR A以形成呋喃基、噻吩基、异噁唑基、噁唑基、噻唑基、噁二唑基、吡咯基、吡唑基、咪唑基、三唑基、或四唑基环部分，其中至多一个R A不为氢；
    L 1,R,R A与权利要求1中所述通式I中的定义相同。
  5. 根据权利要求1所述的化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物，其中，所述通式I的化合物选自式Ii或Ij所示的化合物：
    Figure PCTCN2019109899-appb-100008
    R 1为H、卤素、-OH、-CN、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基；
    X为O、S、CH 2、NH或者N(CH 3)；
    A 6、A 7、A 8、和A 9各自独立地为CR A，其中至多一个R A不为氢；
    或者A 6、A 7、A 8、和A 9之一为N，且其它A 6、A 7、A 8、和A 9为CH；
    或者A 6、A 7、A 8、和A 9之一为N +-O -，且其它A 6、A 7、A 8、和A 9为CH；
    L 1,R,R A与权利要求1中所述通式I中的定义相同。
  6. 根据权利要求1所述的化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物，其中，所述通式I的化合物选自式Ik或Il所示的化合物：
    Figure PCTCN2019109899-appb-100009
    R 1为H、F、Cl、CH 3、CH 2CH 3；
    R为异噁唑基、噁唑基、噻唑基、噁二唑基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、C 3-C 6环烷基、
    Figure PCTCN2019109899-appb-100010
    它们各自独立地为未取代的或被选自F、Cl、甲基、乙基、异丙基和环丙基的1个取代基取代；
    或者，所述通式I的化合物选自式Im或In所示的化合物：
    Figure PCTCN2019109899-appb-100011
    R 1为H、F、Cl、CH 3、CH 2CH 3；
    X为O、S、或者CH 2；
    R为C 1-C 6烷基、C 6-C 10芳基、5-10元杂芳基、3-7元非芳香性杂环基、C 3-C 8环烷基、或C 5-C 8环烯基；所述C 1-C 6烷基、C 6-C 10芳基、5-10元杂芳基、3-7元非芳香性杂环基、C 3-C 8环烷基、或C 5-C 8环烯基各自独立地为未取代的或被1-4个M d取代；
    M d选自F、Cl、甲基、乙基、丙基、丁基、三氟甲基、-(C 1-C 6亚烷基)-OH、异丙基、环丙基、羟基、甲氧基、氨基、甲氨基、二甲氨基、二乙氨基、C 6-C 10芳基、5-10元杂芳基、3-6元非芳香性杂环基；其中所述的C 6-C 10芳基、5-10元杂芳基、3-6元非芳香性杂环基、各自独立地为未取代或被一个或两个各自独立地选自下列的取代基所取代：卤素、C 1-C 4烷基、C 1-C 4烷氧基、-CN。
    或者两个M d和与其相连的环原子一起形成一个3-8元的饱和或者不饱和的环。
  7. 根据权利要求1所述的化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物，其中
    所述通式I的化合物选自如下化合物：
    Figure PCTCN2019109899-appb-100012
    Figure PCTCN2019109899-appb-100013
    Figure PCTCN2019109899-appb-100014
    Figure PCTCN2019109899-appb-100015
    Figure PCTCN2019109899-appb-100016
  8. 一种药物组合物，其包含治疗有效量的选自根据权利要求1-7中任一项所述的通式(I)化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物中的一种或多种，和任选地，可药用载体。
  9. 根据权利要求1-7中任一项所述的化合物、其可药用的盐、立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物在制备治疗对象的疾病或病症或疾病状态的药物中的用途。
  10. 根据权利要求9所述的用途，其中所述疾病或病症或疾病状态选自：炎性肠病，克罗恩氏病、溃疡性结肠炎、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、类风湿性关节炎、脊椎关节炎、痛风、SoJIA、系统性红斑狼疮、干燥综合症、全省性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪肝性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬发性胆管炎、肾炎、乳糜泻、自身免疫ITP、移植排斥、实体器官的缺血再灌注损伤、败血症、全身性炎症反应综合症、脑血管意外、心肌梗死、亨廷顿氏病、阿尔兹海默氏病、帕金森氏病、变应性疾病、哮喘、多发性硬化症、I型糖尿病、韦格纳肉芽肿、肺结节病、白塞氏病、白细胞介素-I转化酶相关的发热综合征、慢性阻塞性肺病、肿瘤坏死因子受体相关的周期性综合症和牙周炎。
PCT/CN2019/109899 2018-11-02 2019-10-08 抑制rip1激酶的杂环酰胺及其用途 WO2020088194A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US17/289,642 US11498927B2 (en) 2018-11-02 2019-10-08 Heterocyclic amide for inhibiting RIP1 kinase and uses thereof
JP2021524263A JP7045526B2 (ja) 2018-11-02 2019-10-08 Ｒｉｐ１キナーゼを阻害する複素環状アミド及びその使用
EP19879421.6A EP3872077B1 (en) 2018-11-02 2019-10-08 Heterocyclic amide for inhibiting rip1 kinase and uses thereof
US18/045,149 US20230167129A1 (en) 2018-11-02 2022-10-08 Heterocyclic amide for inhibiting rip1 kinase and uses thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201811301267 2018-11-02
CN201811301267.9 2018-11-02
CN201910712428.1A CN111138448B (zh) 2018-11-02 2019-08-02 抑制rip1激酶的杂环酰胺及其用途
CN201910712428.1 2019-08-02

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US17/289,642 A-371-Of-International US11498927B2 (en) 2018-11-02 2019-10-08 Heterocyclic amide for inhibiting RIP1 kinase and uses thereof
US18/045,149 Division US20230167129A1 (en) 2018-11-02 2022-10-08 Heterocyclic amide for inhibiting rip1 kinase and uses thereof

Publications (1)

Publication Number Publication Date
WO2020088194A1 true WO2020088194A1 (zh) 2020-05-07

Family

ID=70463472

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/109899 WO2020088194A1 (zh) 2018-11-02 2019-10-08 抑制rip1激酶的杂环酰胺及其用途

Country Status (3)

Country Link
US (1) US20230167129A1 (zh)
JP (1) JP7045526B2 (zh)
WO (1) WO2020088194A1 (zh)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11332451B2 (en) 2018-05-03 2022-05-17 Rigel Pharmaceuticals, Inc. RIP1 inhibitory compounds and methods for making and using the same
CN114989156A (zh) * 2021-05-19 2022-09-02 成都贝诺科成生物科技有限公司 一种受体相互作用蛋白抑制剂及其制备方法和用途
WO2022192533A1 (en) * 2021-03-11 2022-09-15 Rigel Pharmaceuticals, Inc. Heterocyclic rip1 kinase inhibitors
US11479543B2 (en) 2019-09-06 2022-10-25 Rigel Pharmaceuticals, Inc. Heterocyclic RIP1 kinase inhibitors
US11564930B2 (en) 2019-09-06 2023-01-31 Rigel Pharmaceuticals, Inc. RIP1 inhibitory compounds and methods for making and using the same
US11578078B2 (en) 2019-11-07 2023-02-14 Rigel Pharmaceuticals, Inc. Heterocyclic RIP1 inhibitory compounds
US11667643B2 (en) 2020-07-01 2023-06-06 Rigel Pharmaceuticals, Inc. RIP1K inhibitors
WO2023138317A1 (zh) * 2022-01-21 2023-07-27 中国科学院上海药物研究所 具有ripk1抑制活性的化合物、其制备方法及其用途
US11919890B2 (en) 2018-05-03 2024-03-05 ;Eli Lilly and Company RIP1 inhibitory compounds and methods for making and using the same
CN114989156B (zh) * 2021-05-19 2024-07-05 成都贝诺科成生物科技有限公司 一种受体相互作用蛋白抑制剂及其制备方法和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014125444A1 (en) 2013-02-15 2014-08-21 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
CN106573006A (zh) * 2014-08-21 2017-04-19 葛兰素史密斯克莱知识产权发展有限公司 作为药物的rip1激酶抑制剂杂环酰胺
WO2017136727A2 (en) * 2016-02-05 2017-08-10 Denali Therapeutics Inc. Compounds, compositions and methods
WO2019213447A1 (en) * 2018-05-03 2019-11-07 Rigel Pharmaceuticals, Inc. Rip1 inhibitory compounds and methods for making and using the same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014125444A1 (en) 2013-02-15 2014-08-21 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
CN105121432A (zh) 2013-02-15 2015-12-02 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的杂环酰胺
CN106573006A (zh) * 2014-08-21 2017-04-19 葛兰素史密斯克莱知识产权发展有限公司 作为药物的rip1激酶抑制剂杂环酰胺
WO2017136727A2 (en) * 2016-02-05 2017-08-10 Denali Therapeutics Inc. Compounds, compositions and methods
WO2019213447A1 (en) * 2018-05-03 2019-11-07 Rigel Pharmaceuticals, Inc. Rip1 inhibitory compounds and methods for making and using the same

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CAS, no. 1202771-70-7
HARRIS, P.A. ET AL.: "Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases.", J. MED. CHEM., vol. 60, 2 February 2017 (2017-02-02), XP055448328, DOI: 20191219144951A *
J. MED CHEM., vol. 60, 2017, pages 1247
J. MED. CHEM., vol. 60, 2017, pages 1247 - 1261
T. GREENEP. WUTS: "Protecting Groups in Chemical Synthesis", 1999, JOHN WILEY & SONS

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11370765B2 (en) 2018-05-03 2022-06-28 Rigel Pharmaceuticals, Inc. RIP1 inhibitory compounds and methods for making and using the same
US11370764B2 (en) 2018-05-03 2022-06-28 Rigel Pharmaceuticals Inc. RIP1 inhibitory compounds and methods for making and using the same
US11377428B2 (en) 2018-05-03 2022-07-05 Rigel Pharmaceuticals, Inc. RIP1 inhibitory compounds and methods for making and using the same
US11919890B2 (en) 2018-05-03 2024-03-05 ;Eli Lilly and Company RIP1 inhibitory compounds and methods for making and using the same
US11472782B2 (en) 2018-05-03 2022-10-18 Rigel Pharmaceuticals, Inc. RIP1 inhibitory compounds and methods for making and using the same
US11332451B2 (en) 2018-05-03 2022-05-17 Rigel Pharmaceuticals, Inc. RIP1 inhibitory compounds and methods for making and using the same
AU2020341681B2 (en) * 2019-09-06 2024-02-15 Rigel Pharmaceuticals, Inc. RIP1 inhibitory compounds and methods for making and using the same
US11479543B2 (en) 2019-09-06 2022-10-25 Rigel Pharmaceuticals, Inc. Heterocyclic RIP1 kinase inhibitors
JP2022546520A (ja) * 2019-09-06 2022-11-04 ライジェル ファーマシューティカルズ， インコーポレイテッド Ｒｉｐ１阻害化合物ならびにそれを作製および使用するための方法
US11564930B2 (en) 2019-09-06 2023-01-31 Rigel Pharmaceuticals, Inc. RIP1 inhibitory compounds and methods for making and using the same
US11578078B2 (en) 2019-11-07 2023-02-14 Rigel Pharmaceuticals, Inc. Heterocyclic RIP1 inhibitory compounds
US11667643B2 (en) 2020-07-01 2023-06-06 Rigel Pharmaceuticals, Inc. RIP1K inhibitors
WO2022192533A1 (en) * 2021-03-11 2022-09-15 Rigel Pharmaceuticals, Inc. Heterocyclic rip1 kinase inhibitors
WO2022242639A1 (zh) * 2021-05-19 2022-11-24 成都贝诺科成生物科技有限公司 一种受体相互作用蛋白抑制剂及其制备方法和用途
CN114989156A (zh) * 2021-05-19 2022-09-02 成都贝诺科成生物科技有限公司 一种受体相互作用蛋白抑制剂及其制备方法和用途
CN114989156B (zh) * 2021-05-19 2024-07-05 成都贝诺科成生物科技有限公司 一种受体相互作用蛋白抑制剂及其制备方法和用途
WO2023138317A1 (zh) * 2022-01-21 2023-07-27 中国科学院上海药物研究所 具有ripk1抑制活性的化合物、其制备方法及其用途

Also Published As

Publication number Publication date
US20230167129A1 (en) 2023-06-01
JP2021535190A (ja) 2021-12-16
JP7045526B2 (ja) 2022-03-31

Similar Documents

Publication Publication Date Title
CN111138448B (zh) 抑制rip1激酶的杂环酰胺及其用途
WO2020088194A1 (zh) 抑制rip1激酶的杂环酰胺及其用途
AU2018223058B2 (en) Bipyrazole derivatives as jak inhibitors
JP7372255B2 (ja) 免疫調節剤としての複素環式化合物
JP6611799B2 (ja) 新規化合物
JP6665169B2 (ja) 新規化合物αｖβ６インテグリンアンタゴニスト
JP7382973B2 (ja) ピリジニル及びピラジニル－（アザ）インドールスルホンアミド
JP6059723B2 (ja) ４−（８−メトキシ−１−（（１−メトキシプロパン−２−イル）−２−（テトラヒドロ−２Ｈ−ピラン−４−イル）−１Ｈ−イミダゾ［４，５−ｃ］キノリン−７−イル）−３，５−ジメチルイソオキサゾールおよびブロモドメイン阻害剤としてのその使用
WO2017118277A1 (zh) 一种btk激酶抑制剂的结晶形式及其制备方法
EP3983384B1 (en) N-(phenyl)-indole-3-sulfonamide derivatives and related compounds as gpr17 modulators for treating cns disorders such as multiple sclerosis
JP2019509304A (ja) インテグリンアンタゴニストとしてのナフチリジン
KR20180127979A (ko) 화합물 (s)-4-((s)-3-플루오로-3-(2-(5,6,7,8-테트라히드로-1,8-나프티리딘-2-일)에틸)피롤리딘-1-일)-3-(3-(2-메톡시에톡시)페닐) 부탄산의 시트레이트 염
WO2022135610A1 (zh) 四并环化合物及其药物组合物和应用
WO2022017494A1 (zh) 一种哒嗪类衍生物自由碱的晶型及其制备方法和应用
JP2022526553A (ja) 炎症性障害の治療のための新規化合物及びその医薬組成物
WO2019024809A1 (zh) 作为RORγ抑制剂的双环化合物
JP7496440B2 (ja) Ｔｒｋａ阻害剤
CN108484640B (zh) 一种抗肿瘤的细胞凋亡蛋白抑制剂
TW200526633A (en) 4-[(arylmethyl)aminomethyl]piperidine derivatives, their preparation and their therapeutic application
CN115340527B (zh) 一种bcl-xl抑制剂及其制备方法和用途
WO2023138647A1 (zh) 一种含硫异吲哚啉类衍生物的晶型
WO2023236947A1 (zh) 取代的哒嗪-3-甲酰胺化合物作为tyk2抑制剂
TW202140493A (zh) 2-吲哚啉螺環酮類化合物或其鹽、溶劑錯合物之非晶形式或結晶形式
WO2023236814A1 (zh) 一种化合物及其在制备bcl-xl抑制剂中的用途
NZ753637B2 (en) Bipyrazole derivatives as jak inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19879421

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021524263

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019879421

Country of ref document: EP

Effective date: 20210525